CN102690234B - Novel crystal forms of substituted phenylalkanoic acids and process for producing the same - Google Patents

Abstract

In the case of using 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic acid, methyl 3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionate, or methyl 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionate as a medicine, more preferable aspects or improved methods are provided. [Means] Crystals of any compound among 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic acid, methyl 3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionate, and methyl 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionate, and methods of producing the same are provided.

Description

There is crystallization and the manufacture method of the acid of substituent phenylalkane hydrocarbon

The application is divisional application, the international application no of its original application is PCT/JP2007/063896, international filing date is on July 12nd, 2007, China national application number is 200780027080.8, the date entering China is on January 16th, 2009, and denomination of invention is " novel crystal and the manufacture method with the acid of substituent phenylalkane hydrocarbon ".

Technical field

The present invention relates to novel crystallization.Say in further detail, the present invention relates to 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid, 3-[4-(1,2-indane-2-base oxygen base)-3-(1-methyl isophthalic acid H-indazole-5-base)-5-nitrophenyl] novel crystal of any compound or the manufacture method of this crystallization in methyl propionate or 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] methyl propionate.

Background technology

Report is had to claim, 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid has prostaglandin(PG) generation restraining effect and leukotriene produces restraining effect, it is useful for thus disclosing these compounds in the preventing and/or treating of the various diseases associated with inflammation, autoimmune disorder, anaphylactic disease and the pain that are caused by lipid medium, and the manufacture method of these compounds.

Patent documentation 1:WO No. 03/70686 publication

Summary of the invention

The object of the present invention is to provide a kind of using this case compound as mode preferred during medicine and the method through improving.

According to above-mentioned known production method, 3-[3-amino-the 4-(1 of this case compound 1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid (hereinafter sometimes referred to " this case compound 1 ") obtains as follows: at 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] methyl propionate methanol solution in add 2N aqueous sodium hydroxide solution, stir 16 hours in 60 DEG C, after concetrated under reduced pressure reaction mixture, after using 5% aqueous hydrochloric acid furnishing acidity under ice-cooling, extract by ethyl acetate, its organic layer is cleaned with saturated aqueous common salt, after drying, evaporated under reduced pressure is except desolventizing, thus obtain this case compound 1.In this known production method, this case compound obtains with the form of the oily mater of colourless ~ brown.The present inventor thinks, when this case compound 1 is carried out administration as medicine, need a kind of new improvement making operation easier, so carried out various research, confirming this case compound 1 becomes crystallization, thus completes the present invention.

The invention provides the crystallization of this case compound 1, therefore make the operation in formulation operation become easy, and easily make the content of this case compound in each preparation even, this respect is extremely superior.In addition, for the crystallization of this case compound, compared with the situation of oily matter, it is easier in the removal of solvent etc., and fully can carry out the removal of solvent etc., be also suitable for plant-scale manufacture, this respect is also extremely superior.

In addition, the present inventor conducts in-depth research above-mentioned crystallization, found that, the crystallization of A type and the Type B crystallization that demonstrate the novelty of aftermentioned character is there is in this case compound 1, they have excellent character respectively, the present inventor also establishes the method optionally obtaining these crystallizations, thus completes the present invention.

And, according to above-mentioned known production method, 3-[4-(1, 2-indane-2-base oxygen base)-3-(1-methyl isophthalic acid H-indazole-5-base)-5-nitrophenyl] methyl propionate (hereinafter sometimes referred to " this case compound 2 ") obtains as follows: in the ethanolic soln of 3-(the bromo-4-hydroxyl of 3--5-nitrophenyl) methyl propionate and 1-methyl isophthalic acid H-indazole-5-boric acid, add 2M aqueous sodium carbonate, toluene and tetra-triphenylphosphine palladium (0), after stirring 16 hours in 80 DEG C, ethyl acetate is added in reaction mixture, then saturated sodium bicarbonate aqueous solution is used successively, saturated aqueous ammonium chloride, saturated aqueous common salt cleans, after dry organic layer, evaporated under reduced pressure is except desolventizing, and then residue flash column chromatography is refined, thus obtain this case compound 2.Do not mention the form of this case compound in this known production method at all.In this known production method, process operation during not talkative manufacture is easily certain.Further, the present inventor confirms, when this case compound 2 is made medicine, make content uniform in and solvent etc. removal easiness etc. in also have problems.And then the present inventor confirms and can make novel crystallization and obtain this case compound 2, thus completes the present invention.

In addition, according to above-mentioned known production method, 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] methyl propionate is (hereinafter sometimes referred to " this case compound 3 ", and sometimes by " this case compound 1 ", " this case compound 2 " and " this case compound 3 " is collectively referred to as " this case compound ") obtain as follows: in the ethyl acetate/methanol mixing solutions of above-mentioned this case compound 2, add 2800 nickel in Ruan (Raney nickel: Raney nickel), under a hydrogen atmosphere in stirring at room temperature after 6 hours, filter reaction mixture, evaporated under reduced pressure removes the solvent of this filtrate, then by column chromatography, residue is refined, thus obtain this case compound 3.Do not mention the form of this case compound 3 in this known production method, process operation during not talkative manufacture is easily certain at all.Further, the present inventor confirms, when this case compound 3 is made medicine, make content uniform in and solvent etc. removal easiness etc. in also have problems.And then the present inventor confirms and can form novel crystallization and obtain this case compound 3, thus completes the present invention.

That is, the present invention is following technical scheme.

(1) a kind of crystallization, it is 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid, 3-[4-(1,2-indane-2-base oxygen base)-3-(1-methyl isophthalic acid H-indazole-5-base)-5-nitrophenyl] crystallization of any compound in methyl propionate or 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] methyl propionate.

(2) crystallization, it is the crystallization of 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid.

(3) crystallization, it is the crystallization of 3-[4-(1,2-indane-2-base oxygen base)-3-(1-methyl isophthalic acid H-indazole-5-base)-5-nitrophenyl] methyl propionate.

(4) crystallization, it is the crystallization of 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] methyl propionate.

(5) crystallization as described in above-mentioned (1) or (2), it is characterized in that, this crystallization is by 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid formation, and this crystallization is the crystallization of A type, in powder x-ray diffraction spectrum, this A type crystallization is at least the characteristic peak that 6.9 ± 0.2 °, 16.4 ± 0.2 °, 18.2 ± 0.2 °, 25.0 ± 0.2 ° or 27.5 ± 0.2 ° of places have more than 1 at 2 θ.

It should be noted that, 2 θ angles in powder x-ray diffraction spectrum sometimes because various factors there will be permissible some error at measurments, this measured value there will be generally ± 0.3 °, typically for ± 0.2 °, be the degree variation of ± 0.1 ° in preferred mensuration.Therefore, in this specification sheets, the 2 θ angles based on the measured value to specific sample are interpreted as the implication comprising these permissible errors.

(5-1) crystallization as described in above-mentioned (1), (2) or (5), it is characterized in that, this crystallization is by 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid formation, and this crystallization is the crystallization of A type, in powder x-ray diffraction spectrum, this A type crystallization is that 6.9 ± 0.2 °, 14.4 ± 0.2 °, 16.4 ± 0.2 °, 18.2 ± 0.2 °, 25.0 ± 0.2 ° and 27.5 ± 0.2 ° of places have characteristic peak at 2 θ.

(6) crystallization as described in above-mentioned (1), (2), (5) or (5-1), it is characterized in that, this crystallization is by 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid formation, and this crystallization is the crystallization of A type, this A type crystallization has the endotherm(ic)peak of about 182 DEG C in Differential Scanning Calorimeter analysis (heat-up rate is 10 DEG C/min).

It should be noted that, endotherm(ic)peak in Differential Scanning Calorimeter analysis is the intrinsic physical property that the crystallization of this case compound just has originally, but in the mensuration of reality, except error at measurment, cause fusing point change owing to being mixed into the reasons such as the impurity of permissible amount sometimes, this possibility is also irrefragable.Therefore, those skilled in the art can fully understand the measured value of the endotherm peak temperature in the present invention can with which kind of degree change, for example, the error that it is contemplated that is, being about ± 5 DEG C in some cases, is about ± 3 DEG C typically, is about ± 2 DEG C in preferred mensuration.

(7) crystallization as described in above-mentioned (1), (2), (5), (5-1) or (6), it is characterized in that, this crystallization is by 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid formation, and this crystallization is the crystallization of A type, in infrared absorption spectrum, this A type crystallization is in wave number 3361cm ^-1, 2938cm ^-1, 1712cm ^-1, 1204cm ^-1, 1011cm ^-1and 746cm ^-1near there is obvious infrared absorption band.

Note, allows some error at measurments once in infrared absorption spectrum wave number, also thinks in the present invention and can comprise this error.Those skilled in the art can fully understand described error degree, such as, with reference to European Pharmacopoeia (ヨ ー ロ ッ パ officina side) the 4th edition, this pharmacopeia indicates such error degree, namely, in the validation test utilizing infrared absorption spectrum to carry out with reference to compared with spectrum, wave-number scale value (wave number ス ケ mono-Le) ± 0.5% within consistent.In the present invention, this is not particularly limited, can with reference to their error imputed usually, such as, can enumerate as a yardstick, be about ± 0.8% relative to the measured value of wave-number scale value, be preferably about ± 0.5%, be particularly preferably ± the change of about 0.2%.

(7-1) 3-[3-amino-4-(1 as described in any one of above-mentioned (5) ~ (7), 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] the A type crystallization of propionic acid, wherein, the crystallization purity of described crystallization is at least more than 90 % by weight.

It should be noted that, though write in above-mentioned chapters and sections is (5) ~ (7), but it is the implication of the invention also comprising branch numbering according to the order of layout, specifically, (5) ~ (7) refer to (5), (5-1), (6), (7).Also identical hereinafter.

(8) crystallization as described in above-mentioned (1) or (2), it is characterized in that, this crystallization is by 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid formation, and this crystallization is Type B crystallization, in powder x-ray diffraction spectrum, this Type B crystallization is at least the characteristic peak that 15.9 ± 0.2 °, 17.3 ± 0.2 °, 22.2 ± 0.2 ° or 22.9 ± 0.2 ° of places have more than 1 at 2 θ.

(8-1) crystallization as described in above-mentioned (1), (2) or (8), it is characterized in that, this crystallization is by 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid formation, and this crystallization is Type B crystallization, in powder x-ray diffraction spectrum, this Type B crystallization is that 14.4 ± 0.2 °, 15.9 ± 0.2 °, 17.3 ± 0.2 °, 22.2 ± 0.2 ° and 22.9 ± 0.2 ° of places have characteristic peak at 2 θ.

(9) crystallization as described in above-mentioned (1), (2), (8) or (8-1), it is characterized in that, this crystallization is by 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid formation, and this crystallization is Type B crystallization, this Type B crystallization has the endotherm(ic)peak of about 203 DEG C in Differential Scanning Calorimeter analysis (heat-up rate is 10 DEG C/min).

(10) crystallization as described in above-mentioned (1), (2), (8), (8-1) or (9), it is characterized in that, this crystallization is by 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid formation, and this crystallization is Type B crystallization, in infrared absorption spectrum, this Type B crystallization is in wave number 2939cm ^-1, 1720cm ^-1, 1224cm ^-1, 1016cm ^-1and 751cm ^-1near there is obvious infrared absorption band.

(10-1) 3-[3-amino-4-(1 as described in any one of above-mentioned (8) ~ (10), 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] the Type B crystallization of propionic acid, wherein, the crystallization purity of described crystallization is at least more than 90 % by weight.

(10-2) crystallization as described in above-mentioned (1) or (3), it is characterized in that, this crystallization is by 3-[4-(1,2-indane-2-base oxygen base)-3-(1-methyl isophthalic acid H-indazole-5-base)-5-nitrophenyl] methyl propionate formation, in powder x-ray diffraction spectrum, this crystallization is at least the characteristic peak that 7.6 ° ± 0.2 °, 15.3 ° ± 0.2 °, 18.0 ° ± 0.2 °, 21.3 ° ± 0.2 ° and 26.9 ° ± 0.2 ° place have more than 1 at 2 θ.

(10-3) crystallization as described in above-mentioned (1), (3) or (10-2), it is characterized in that, this crystallization is by 3-[4-(1,2-indane-2-base oxygen base)-3-(1-methyl isophthalic acid H-indazole-5-base)-5-nitrophenyl] methyl propionate formation, in powder x-ray diffraction spectrum, this crystallization is that 7.6 ± 0.2 °, 15.3 ± 0.2 °, 18.0 ± 0.2 °, 21.3 ± 0.2 ° and 26.9 ± 0.2 ° of places have characteristic peak at 2 θ.

(10-4) crystallization as described in above-mentioned (1) or (4), it is characterized in that, this crystallization is by 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] methyl propionate formation, in powder x-ray diffraction spectrum, this crystallization is at least the characteristic peak that 8.6 ± 0.2 °, 12.7 ± 0.2 °, 17.2 ± 0.2 °, 17.6 ± 0.2 °, 18.9 ± 0.2 ° and 21.0 ± 0.2 ° of places have more than 1 at 2 θ.

(10-5) crystallization as described in above-mentioned (1), (4) or (10-4), it is characterized in that, this crystallization is by 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] methyl propionate formation, in powder x-ray diffraction spectrum, this crystallization is that 8.6 ± 0.2 °, 12.7 ± 0.2 °, 17.2 ± 0.2 °, 17.6 ± 0.2 °, 18.9 ± 0.2 ° and 21.0 ± 0.2 ° of places have characteristic peak at 2 θ.

(11) a kind of pharmaceutical composition, it is characterized in that, this pharmaceutical composition contains the 3-[3-amino-4-(1 described in any one of above-mentioned (1) ~ (10-5), 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] crystallization of propionic acid or its A type crystallization or Type B crystallization, or 3-[4-(1, 2-indane-2-base oxygen base)-3-(1-methyl isophthalic acid H-indazole-5-base)-5-nitrophenyl] crystallization of methyl propionate, or 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] methyl propionate crystallization in any one crystallization as effective constituent, this pharmaceutical composition is also containing pharmaceutically useful carrier.

(12) pharmaceutical composition as described in above-mentioned (11), is characterized in that, described pharmaceutically useful carrier is dry thing, and described pharmaceutical composition is drying agent.

(13) a kind of pharmaceutical composition, it is characterized in that, this pharmaceutical composition contains crystallization purity and is at least the A type crystallization of more than 90 % by weight as effective constituent, this A type crystallization is the 3-[3-amino-4-(1 described in any one of above-mentioned (5) ~ (7), 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] the A type crystallization of propionic acid, this pharmaceutical composition is also containing pharmaceutically useful carrier.

(14) a kind of pharmaceutical composition, it is characterized in that, this pharmaceutical composition contains crystallization purity and is at least the Type B crystallization of more than 90 % by weight as effective constituent, this Type B crystallization is the 3-[3-amino-4-(1 described in any one of above-mentioned (8) ~ (10), 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] the Type B crystallization of propionic acid, this pharmaceutical composition is also containing pharmaceutically useful carrier.

(15) 3-[3-amino-4-(1 described in any one of above-mentioned (5) ~ (7-1), 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] manufacture method of A type crystallization of propionic acid, it is characterized in that, by to 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base)-phenyl] propionic acid solution in the basic conditions in acid adding, generate by this 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base)-phenyl] propionic acid formed crystallization, then this crystallization is obtained.

(16) 3-[3-amino-4-(1 as described in above-mentioned (15), 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] manufacture method of A type crystallization of propionic acid, it is characterized in that, this 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base)-phenyl] solution in the basic conditions of propionic acid is 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] alkaline hydrolysate of lower alkyl esters of propionic acid.

(16-1) 3-[3-amino-4-(1 as described in any one of above-mentioned (5) ~ (7-1), 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] manufacture method of A type crystallization of propionic acid, it is characterized in that, to 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] after the lower alkyl esters of propionic acid carries out basic hydrolysis, acid adding in reaction solution, generate by this 3-[3-amino-4-(1 thus, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base)-phenyl] propionic acid formed crystallization, then this crystallization is obtained.

(17) 3-[3-amino-4-(1 as described in any one of above-mentioned (8) ~ (10-1), 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] manufacture method of Type B crystallization of propionic acid, it is characterized in that, by 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid is dissolved in and is selected from by acetone, methylene dichloride, methyl alcohol, ethyl acetate, in any one or two or more solvents in the group of methyl alcohol/acetic acid mixture and acetonitrile composition, this 3-[3-amino-4-(1 is made from the solution dissolved, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid crystallization.

(18) manufacture method of the crystallization as described in any one of above-mentioned (8) ~ (10-1), it is characterized in that, to 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base)-phenyl] propionic acid solution in the basic conditions in acid adding, be about to generate by this 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base)-phenyl] propionic acid formed crystallization before, add the Type B crystallization of this compound as crystal seed, obtain the Type B crystallization of this compound thus.

(18-1) 3-[3-amino-4-(1 as described in above-mentioned (18), 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] manufacture method of Type B crystallization of propionic acid, it is characterized in that, this 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base)-phenyl] solution in the basic conditions of propionic acid is 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] alkaline hydrolysate of lower alkyl esters of propionic acid.

(18-2) manufacture method of the crystallization described in any one of above-mentioned (8) ~ (10-1), it is characterized in that, to 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] after the lower alkyl esters of propionic acid carries out basic hydrolysis, acid adding in reaction solution, be about to generate by this 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base)-phenyl] propionic acid form crystallization before, the Type B crystallization of this compound is added as crystal seed in reaction solution, obtain the Type B crystallization of this compound thus.

(19) 3-[4-(1, 2-indane-2-base oxygen base)-3-(1-methyl isophthalic acid H-indazole-5-base)-5-nitrophenyl] manufacture method of crystallization of methyl propionate, it is characterized in that, with being selected from by toluene, ethyl acetate, tetrahydrofuran (THF), acetone, glycol dimethyl ether, any one or two or more dissolution with solvents 3-[4-(1 in the group of methyl alcohol composition, 2-indane-2-base oxygen base)-3-(1-methyl isophthalic acid H-indazole-5-base)-5-nitrophenyl] methyl propionate, adding in the solution dissolved is selected from by heptane, diisopropyl ether, Virahol, t-butyl methyl ether, any one or two or more solvents in the group of water composition, generate crystallization.

(19-1) manufacture method as described in above-mentioned (19), it is characterized in that, in powder x-ray diffraction spectrum, it is the characteristic peak of more than at least 1 among 7.6 ± 0.2 °, 15.3 ± 0.2 °, 18.0 ± 0.2 °, 21.3 ± 0.2 ° and 26.9 ± 0.2 ° that this crystallization has 2 θ, and representational is that this crystallization has all these peaks.

(20) 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] manufacture method of crystallization of methyl propionate, it is characterized in that, with being selected from by toluene, ethyl acetate, tetrahydrofuran (THF), any one or two or more dissolution with solvents 3-[3-amino-4-(1 in the group of acetone composition, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] methyl propionate, adding in the solution dissolved is selected from by heptane, Virahol, methyl alcohol, any one or two or more solvents in the group of water composition, generate crystallization.

(20-1) manufacture method as described in above-mentioned (20), it is characterized in that, in powder x-ray diffraction spectrum, it is the characteristic peak of more than at least 1 among 8.6 ± 0.2 °, 12.7 ± 0.2 °, 17.2 ± 0.2 °, 17.6 ± 0.2 °, 18.9 ± 0.2 ° and 21.0 ± 0.2 ° that this crystallization has 2 θ, and representational is that this crystallization has all these peaks.

The advantage of crystallization in formulation operation of this case compound 1 is comparatively large, and the content being such as easy to this case compound made in each preparation is even, etc., and, compared with the situation of oily matter, this crystallization, easily except being also favourable in desolventizing etc., is also suitable for plant-scale manufacture.

As the crystallization of this case compound 1 used in ad hoc fashion of the present invention, the crystallization of A type can be enumerated as preference.The A type crystallization of this case compound 1 is the crystallization of any one or plural combination defined in following various characteristic, and described various characteristic is the various characteristics confirmed in the above-mentioned various characteristic of technical scheme (5) ~ (7-1) or the embodiment, test example etc. of present specification.Through confirming, except the advantage that the crystallization of above-mentioned this case compound 1 has, because this A type crystallization also shows certain proterties, thus with without the common crystallization phases ratio controlled, it is not only as preparation or to play in drug effect but also show excellent character in manufacturing processed etc.It should be noted that, confirmed above-mentioned A type crystallization such as with Type B crystallization phases ratio described later, in water solvent, have higher solvability, from the viewpoint of this, the crystallization of A type is also preferred.

In order to farthest play the excellent effect that the crystallization of A type has, preferred use is essentially the A type crystallization of A type crystallization, as such A type crystallization, the crystallization purity (percentage ratio) can enumerating the crystallization of A type is generally more than about 90 % by weight, is preferably more than 95 % by weight, is more preferably more than 97 % by weight, more preferably more than 99 % by weight, is particularly preferably about 100 % by weight.Further, in some cases, be preferably more than 93 % by weight, more preferably more than 98 % by weight, be particularly preferably more than 99.5 % by weight.Further, when being used as the medicine of this case, more than 80 % by weight are generally.Further, as the optimal way of A type crystallization, the crystallization in fact not containing the crystal type except A type can also be enumerated." in fact not containing " refers to following implication: the crystal type content beyond the crystallization of A type is preferably less than 10 % by weight, be more preferably less than 5 % by weight, more preferably less than 3 % by weight, be particularly preferably less than 1 % by weight, most preferably completely containing the crystal type beyond the crystallization of A type.

Further, as the crystallization used in another mode of the present invention, Type B crystallization can also be enumerated as preference.The Type B crystallization of this case compound 1 is the crystallization of any one or plural combination defined in following various characteristic, and described various characteristic is the various characteristics confirmed in the above-mentioned various characteristic of technical scheme (8) ~ (10-1) or the embodiment, test example etc. of present specification.Except the advantage that the crystallization of above-mentioned this case compound 1 has, this Type B crystallization also shows certain proterties, thus with without the common (Unit な Ru controlled) crystallization phases ratio, it is as preparation or to play in drug effect and show excellent character in manufacturing processed etc.Further, higher than this Type B crystallization filterableness with A type crystallization phases, flow characteristics is also further improved in addition, thus can expect, when a large amount of manufacture Type B crystallization, can shorten the time required in such as filter progress and/or dehydration procedure etc.Further, Type B crystallization is also more preferably when manufacturing drying agent, solid preparation.Also confirmed the Type B crystallization after filter dehydration lower than the water ratio of the A type crystallization after filter dehydration, particularly when manufacturing in a large number, Type B crystallization is in the time shortened needed for drying and reduce Worth Expecting in heat energy, and can think that Type B crystallization is preferred.In addition, also think that this Type B crystallization and A type crystallization phases are than having morphological stability good in fact.In order to farthest play the superior effect that Type B crystallization has, preferred use is essentially the Type B crystallization of Type B crystallization, as such Type B crystallization, the crystallization purity (percentage ratio) can enumerating Type B crystallization is generally more than about 90 % by weight, is preferably more than 95 % by weight, is more preferably more than 97 % by weight, more preferably more than 99 % by weight, is particularly preferably about 100 % by weight.Further, in some cases, be preferably more than 93 % by weight, more preferably more than 98 % by weight, be particularly preferably more than 99.5 % by weight.Further, when being used as the medicine of this case, more than 80 % by weight are generally.Further, as the optimal way of Type B crystallization, the crystallization in fact not containing the crystal type beyond Type B can also be enumerated." in fact not containing " refers to following implication: the crystal type content beyond Type B crystallization is preferably less than 10 % by weight, be more preferably less than 5 % by weight, more preferably less than 3 % by weight, be particularly preferably less than 1 % by weight, most preferably do not contain completely.

It should be noted that, as the crystallization purity (percentage ratio) of A type crystallization, as long as the crystallization of A type crystallization is existed weight to be multiplied by 100 again divided by the weight that exists of this case compound 1.Herein, there is the measuring method that there is weight of weight and this case compound 1 in the crystallization as the crystallization of A type, can use following any means, can also use and carry out the measuring method of appropriate change further to these methods.

By the way, utilize some measuring method may occur unnecessary error at measurment, now also preferably use the standard substance of known quantity to confirm miss extent and correct.Such as, in the present invention, particularly preferably by being multiplied by 100 times by the measured value of crystallization again divided by the measured value of this case compound 1 and the value obtained represents crystallization purity, the measured value of described crystallization be the measuring method analyzed based on Differential Scanning Calorimeter (particularly, concrete condition determination described in present specification can be enumerated as particularly preferred example) calculate, the measured value of described this case compound 1 is by the mensuration based on HPLC (particularly, concrete condition determination described in present specification can be enumerated as particularly preferred example) calculate.And, crystallization purity (percentage ratio) explanation also with above-mentioned of Type B crystallization is identical, suitably can change its measuring method, particularly preferably by being multiplied by 100 times by the measured value of crystallization again divided by the measured value of this case compound 1 and the value obtained represents crystallization purity, the measured value of described crystallization be the measuring method analyzed based on Differential Scanning Calorimeter (especially, concrete condition determination described in present specification can be enumerated as particularly preferred example) calculate, the measured value of this case compound 1 be based on HPLC mensuration (especially, concrete condition determination described in present specification can be enumerated as particularly preferred example) calculate.

Generally speaking, the amount of each crystallization can be analyzed by Differential Scanning Calorimeter or measure powder x-ray diffraction spectrum, infrared absorption spectrum, solid ¹³the intensity of the characteristic peak in C-NMR spectrum, Raman spectrum etc. is obtained, especially as described above, measure the A type crystallization of this case compound 1 and Type B crystallization there is rate time, can enumerate and utilize Differential Scanning Calorimeter analysis to carry out method for measuring as preference.Be specifically described for the A type crystallization of this case compound 1, utilizing the Differential Scanning Calorimeter analysis of suitable heat-up rate (as suitable heat-up rate, such as can enumerate 50 DEG C/min) in, about crystallization, use pure A type crystallization as standard substance, the area (mJ) of the endotherm(ic)peak near the weight (mg) of these standard substance and produced by the melting of A type crystallization about 185 DEG C is mapped, make typical curve, the area (mJ) of the endotherm(ic)peak of sample to be tested near about 185 DEG C is substituted into above-mentioned typical curve, thus the amount of A type crystallization can be obtained.Further, the Type B crystallization for this case compound 1 also similarly can obtain amount.That is, about crystallization, use pure Type B crystallization as standard substance, the endotherm(ic)peak that measurement example is analyzed as the Differential Scanning Calorimeter of Type B crystallization as being usually about the endotherm(ic)peak near 205 DEG C.

In measuring method beyond Differential Scanning Calorimeter analysis, namely at powder x-ray diffraction spectrum, infrared absorption spectrum, solid ¹³in the measuring methods such as C-NMR spectrum, Raman spectrum, also can amount by using standard substance production standard curve to obtain target crystal type in the same manner as Differential Scanning Calorimeter analysis.

Particularly utilize the measuring method beyond Differential Scanning Calorimeter analysis, namely utilize powder x-ray diffraction spectrum, infrared absorption spectrum, solid ¹³when the measuring methods such as C-NMR spectrum, Raman spectrum calculate the amount of target crystal type, the characteristic peak of each crystal type suitably can be selected to carry out production standard curve, thus obtain the amount of target crystal type.

It should be noted that, as the spectrometric optical system of use powder x-ray diffraction, general focusing optical system or collimated beam method optical system can be enumerated.Used optical system being not particularly limited, when for guaranteeing resolution and intensity, preferably using focusing optical system to measure.Further, when for suppressing orientation (namely due to the shape (needle-like, sheet etc.) of crystallization towards the phenomenon of certain orientation), collimated beam method optical system is preferably used to measure.As the determinator of focusing optical system, XRD-6000 (Shimadzu Seisakusho Ltd.'s manufacture) or MultiFlex (company of science manufactures) etc. can be enumerated.Further, as the determinator of collimated beam method optical system, XRD-7700 (Shimadzu Seisakusho Ltd.'s manufacture) or R1NT2200Ultima+/PC (company of science manufactures) etc. can be enumerated.

Further, when needing the amount measuring this case compound 1 in preparation, usually use HPLC easier and preferred.Namely, such as this case compound 1, the standard substance of this case compound 1 that chemical purity can be used known utilize HPLC method to measure, and make the typical curve of this case compound 1, carry out quantitatively the amount of this case compound 1 in sample according to this typical curve.

About the quantivative approach based on HPLC of above-mentioned this case compound 1 and the measuring method of crystallization are applicable to this case compound 2 described later or this case compound 3 too.Such as, can carry out as HPLC condition under condition same as described above, the measuring method based on Differential Scanning Calorimeter analysis also can use respective feature endotherm(ic)peak to measure.Further, respective crystallization purity also can be carried out mensuration to obtain in the same manner as described above.In above-mentioned mensuration, be used as to be used as in the A type crystallization of pure this case compound 1 of standard substance and the manufacture method of Type B crystallization and crystallization described later the A type crystallization of pure this case compound 1 of crystal seed and Type B crystallization can distinguish and obtain as follows: after preferably obtaining according to each method in the embodiment of the present application 3,4 or 5 respectively, the therefrom crystallization of special selected shape excellence, then analyzed by Differential Scanning Calorimeter, select the crystallization showing each distinctive single endotherm(ic)peak, thus obtain each crystallization.The Type B crystallization obtained according to the various methods of embodiment 6 ~ 7 can also be used as standard substance.And, the Type B crystallization obtained according to the various methods of embodiment 6 ~ 7 can also be used as the crystal seed for obtaining pure Type B crystallization.In addition, when being mixed into Type B crystallization in the crystallization of A type, the quantitative values of this A type crystallization utilizing Differential Scanning Calorimeter analysis to obtain may determined must lower than the quantitative values of common standard substance A type crystallization.The degree reduced changes with the incorporation rate of Type B crystallization in the crystallization of A type, and such as, when the incorporation rate of Type B crystallization is within 10%, the quantitative values of A type crystallization may exist the error of common about 10%.Further, when Type B crystallization incorporation rate close to 50% time, may exist maximum reach about 20% error.Conversely, when being mixed into the crystallization of A type in Type B crystallization, its quantitative values may higher than the crystallization of standard substance Type B, and the degree exceeded changes with the incorporation rate of A type crystallization in Type B crystallization, similarly, such as, when the incorporation rate of A type crystallization is within 10%, may there is the error of common about 10% in the quantitative values of Type B crystallization, and, when the crystallization of A type incorporation rate close to 50% time, may exist maximum reach about 20% error.Under the not extra high common state of mutual incorporation rate, the crystallization purity of the crystallization of A type or Type B crystallization comprises the error of about about 10%.When carrying out quantitative, have and utilize the standard substance giving the blend level thought to make typical curve to carry out quantitative method.And, in order to clearly judge incorporation rate further, suitably can prepare the mixture of the known blend level of A type crystallization standard substance and Type B crystallization standard substance, the area (mJ) of the endotherm(ic)peak produced according to the melting of the blend level (percentage ratio) of object crystallization and this crystallization carrys out production standard curve relative to the percentage ratio of all peak areas, is known the mixture ratio of this crystallization in determinand by this typical curve.

Further, in the measuring method beyond Differential Scanning Calorimeter analysis, namely at powder x-ray diffraction spectrum, infrared absorption spectrum, solid ¹³in the measuring methods such as C-NMR spectrum, Raman spectrum, the known standard substance mixture of blend level also can be used to make typical curve, clearly judge mixture ratio according to this typical curve.

Accompanying drawing explanation

Fig. 1 is the powder x-ray diffraction spectrum of this case compound 2 crystallization.In figure, the longitudinal axis represents intensity (CPS), and transverse axis represents 2 θ (°).

Fig. 2 is the powder x-ray diffraction spectrum of this case compound 3 crystallization.In figure, the longitudinal axis represents intensity (CPS), and transverse axis represents 2 θ (°).

Fig. 3 is the powder x-ray diffraction spectrum of the A type crystallization of this case compound 1.In figure, the longitudinal axis represents intensity (CPS), and transverse axis represents 2 θ (°).

Fig. 4 is the Differential Scanning Calorimeter analysis of the A type crystallization of this case compound 1.In figure, the longitudinal axis represents mW, and transverse axis represents temperature (DEG C).

Fig. 5 is the infrared absorption spectrum of the A type crystallization of this case compound 1.In figure, the longitudinal axis represents transmitance (%), and transverse axis represents cm ^-1.

Fig. 6 is the powder x-ray diffraction spectrum of the Type B crystallization of this case compound 1.In figure, the longitudinal axis represents intensity (CPS), and transverse axis represents 2 θ (°).

Fig. 7 is the Differential Scanning Calorimeter analysis of the Type B crystallization of this case compound 1.In figure, the longitudinal axis represents mW, and transverse axis represents temperature (DEG C).

Fig. 8 is the infrared absorption spectrum of the Type B crystallization of this case compound 1.In figure, the longitudinal axis represents transmitance (%), and transverse axis represents cm ^-1.

Fig. 9 represents the typical curve in the Differential Scanning Calorimeter analysis of the A type crystallization of this case compound 1.In figure, the longitudinal axis represents area (mJ), and transverse axis represents weight (mg).

Figure 10 represents the typical curve in the Differential Scanning Calorimeter analysis of the Type B crystallization of this case compound 1.In figure, the longitudinal axis represents area (mJ), and transverse axis represents weight (mg).

Figure 11 is the photo being used as accompanying drawing of the crystal form of the A type crystallization of display this case compound 1, and Figure 11 is scanning electron microscope (SEM) photo.

Figure 12 is the photo being used as accompanying drawing of the crystal form of the Type B crystallization of display this case compound 1, and Figure 12 is scanning electron microscope (SEM) photo.

Embodiment

[manufacture method of the A type crystallization of this case compound 1]

As the manufacture method of the A type crystallization of this case compound 1, following method can be enumerated: acid adding in the solution under the alkaline condition of this case compound 1, generates the crystallization be made up of this case compound 1, then obtains this crystallization.

Namely, solution under alkaline condition for this case compound 1 of the present invention is not particularly limited, as long as the solution that this compound dissolves in the basic conditions, herein, should can be oily by this compound dissolved, any one in solid state (comprise various crystal type, armorphous) or their mixture.It should be noted that, this case compound 1 can be prepared according to the method for International Publication WO No. 03/70686 publication.

As the alkali for the preparation of the solution under above-mentioned alkaline condition, preferred mineral alkali.That is, can enumerate the alkali metal bases etc. such as such as sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium methylate, potassium tert.-butoxide, preferred sodium hydroxide, potassium hydroxide etc., can enumerate sodium hydroxide as particularly preferred example.Also the alkaline solution in advance these alkali being made the solution states such as alcohols such as water or methyl alcohol, ethanol, the trimethyl carbinol can be used, when the previously prepared aqueous solution containing certain density alkali uses, particularly preferably operate like this owing to being easy to regulation addition etc.Further, when using concentrated basic solution, higher neutralization heat can be produced owing to also considering when adding acid afterwards, therefore can enumerate the situation of the aqueous solution of the alkali of use 0.5 ~ 2N as example very preferably.

For the amount of added alkali, relative to this compound of 1 equivalent, lower limit is generally more than 0.8 equivalent, is preferably more than 0.9 equivalent, is more preferably more than 1.0 equivalents.Relative to this compound of 1 equivalent, the upper limit is generally below 3.0 equivalents, is preferably below 2.0 equivalents.

As the solvent for making compound dissolve together with alkali, preferably enumerating polar solvent, the alcohols such as methyl alcohol, ethanol can be enumerated particularly; The ethers such as tetrahydrofuran (THF), dioxane; Acetone etc., as required, these also can be used in combination.Among these, preferably water, methyl alcohol, ethanol, tetrahydrofuran (THF) etc., particularly preferably water, methyl alcohol, ethanol etc.Further, very preferably by the situation that water and methanol mixed use, for making the water after containing the solution of alkali: the blending ratio of methyl alcohol, can 1: 20 ~ 10: 1 be enumerated, being preferably the ratio of 1: 10 ~ 1: 1.

In solution under above-mentioned alkaline condition, can heat under the temperature below the boiling point of solvent, and, when there is insolubles, wait operation removing insolubles preferably by filtration.

As the acid added in above-mentioned solution, as long as the throw out of the crystallization generated by adding acid can not be entered into, can be then the random order in liquid, solid state and gas shape, be preferably solution shape or gas, the acid of solution shape can be enumerated as particularly preferred example.

Further, the kind about acid can enumerate various organic acid and mineral acid, but acid used is in order to neutralization bases, and its acid degree must higher than the acid degree of this case compound, the mineral acids such as preferred hydrochloric acid, sulfuric acid, phosphoric acid, particularly preferably hydrochloric acid.These acid also can use the liquid making the solution shapes such as alcohols such as water or methyl alcohol, ethanol, the trimethyl carbinol in advance, when the previously prepared aqueous acid containing constant density uses, owing to being easy to regulation addition etc. and preferably operation like this.Further, when using concentrated acidic solution, higher neutralization heat can be produced owing to considering, the situation of the acidic aqueous solution of use 0.5 ~ 2N can be enumerated as particularly preferred example.

Be not particularly limited the amount of added acid, as long as add the degree that crystallization fully generates to, relative to 1 equivalent alkali, can enumerate usual addition is more than 0.8 equivalent, preferably adds more than 0.9 equivalent.Further, about 1 equivalent is particularly preferably added.Further, be not particularly limited the upper limit, relative to 1 equivalent alkali, can enumerate usual addition is below 1.5 equivalents, can enumerate below 1.2 equivalents as preference.

As the method for adding acid, can enumerate: (1) disposable interpolation, (2) point are added for several times, (3) add continuously for a long time the method such as to drip, etc., preferably with the method that the methods such as dropping are added continuously for a long time.Preferably stir when adding acid.Interpolation speed is different from the difference of the alkali concn in the solution under the amount of used compound, alkaline condition, the kind of acid used, the concentration of acidic solution, when using the hydrochloric acid of 0.5 ~ 2N, the method by the time interpolation total amount of 1 hour ~ 6 hours can be enumerated.

For temperature when adding sour, the upper limit is preferably less than 60 DEG C, is more preferably less than 50 DEG C, and more preferably less than 45 DEG C, lower limit is preferably more than 0 DEG C, is more preferably more than 10 DEG C, more preferably more than 25 DEG C.

When generated crystallization will be obtained, within after addition of the acid 24 hours can be enumerated usually, preferably carry out within 10 hours within 20 hours, particularly preferably.Further, although also crystallization can be obtained immediately after addition of the acid, after 1 hour preferably after interpolation, particularly preferably within 3 hours, obtaining crystallization after adding later.

As gathering the method for crystallization separated out, filtrations can be utilized, incline and the known method such as to strain to obtain crystallization, preferably filtration usually.Further, after collecting crystallization by filtration, polar solvent (such as water, methyl alcohol, ethanol or their mixed solution) can be utilized to clean crystallization, and this is effective as going deimpurity operation.As purging method, preferably use the method for the crystallization on polar solvent rinsing filter.Further, being also preferably as follows method: crystallization dropped in polar solvent (such as water, methyl alcohol, ethanol or their mixed solution) and make suspension, after fully stirring this suspension, again obtaining crystallization by filtering.And then, particularly preferably carry out these 2 kinds of purging methods above-mentioned.The crystallization obtained can utilize the drying means (such as drying under reduced pressure, heating under reduced pressure is dry, normal heating is dry, air-dry) usually carried out to come dry.

The ratio of solvent when kind, the mixed solvent of the precipitation concentration of adding the final compound after acid also according to used solvent and different, the lower limit of this precipitation concentration is generally more than 1w/v%, preferably more than 5w/v%.The upper limit is preferably below 30w/v%, is preferably below 20w/v%.

It should be noted that, can thinking that adding a small amount of A crystallization as the mode of crystal seed when generating crystallization is also preferred mode.

As example preferred among above-mentioned manufacture method, following example can be enumerated.In the example of 3 kinds of following manufacture method, the amount of the alkali used, add whipping temp before acid, the amount of acid of interpolation and the churning time of adding after acid and can adopt above-mentioned preference.

By 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid is dissolved in containing being the sodium hydroxide of 0.8 ~ 3.0 equivalent or the water of potassium hydroxide relative to it, methyl alcohol, ethanol, solution is obtained in tetrahydrofuran (THF) or their mixed solvent, under agitation in the temperature of 10 ~ 50 DEG C, with methods such as droppings, adding for a long time continuously in obtained solution relative to 1 equivalent alkali is the hydrochloric acid of 0.8 ~ 1.5 equivalent, sulfuric acid or phosphorus aqueous acid, further stirring 1 ~ 24 hour, obtain the method for crystallization.

Above-claimed cpd is dissolved in and obtains solution containing in the water relative to 1 equivalent above-claimed cpd being the sodium hydroxide of 0.9 ~ 2.0 equivalent, methyl alcohol, ethanol or their mixed solvent, in the temperature of 25 ~ 45 DEG C under stirring, with the time of 1 hour ~ 6 hours, adding in obtained solution relative to 1 equivalent alkali is the aqueous hydrochloric acid of 0.5 ~ 2N of 0.9 ~ 1.2 equivalent, further stirring 3 ~ 24 hours, obtains the method for crystallization.

Above-claimed cpd is dissolved in containing being obtain solution in 0.5 ~ 2N aqueous sodium hydroxide solution of 0.9 ~ 2.0 equivalent and methyl alcohol relative to 1 equivalent above-claimed cpd, in the temperature of 25 ~ 45 DEG C under stirring, with the time of 1 hour ~ 6 hours, interpolation is the aqueous hydrochloric acid of 0.5 ~ 2N of 0.9 ~ 1.2 equivalent relative to 1 equivalent alkali, further stirring 3 ~ 24 hours, obtains the method for crystallization.

And, solution under the alkaline condition of above-mentioned this case compound 1 can be the alkaline hydrolysate of the lower alkyl esters of 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid.That is, as the other manufacture method of A type crystallization, following method can be enumerated.

By 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] lower alkyl esters of propionic acid is in a solvent after alkaline hydrolysis, acid adding in solution under this alkaline condition, thus the method obtaining crystallization.

As above-mentioned " lower alkyl esters ", the carboxylicesters that carbonatoms is the alkyl of 1 ~ 4 can be enumerated, be the alkyl of 1 ~ 4 as carbonatoms, any one in methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl can be enumerated.Wherein particularly preferably methyl and ethyl.

The lower alkyl esters of 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid can be prepared according to the method for International Publication WO No. 03/70686 publication.

As the alkali used when preparing the alkaline hydrolysate of above-claimed cpd, can use above-mentioned for making solution be in alkali under alkaline condition.

The consumption of alkali is generally more than 1 equivalent relative to 1 equivalents of compound.The upper limit is generally below 10 equivalents relative to this compound of 1 equivalent, is preferably below 3 equivalents, is particularly preferably below 2 equivalents.

Solvent does not normally hinder the inert media reacting and carry out, and preferably reacts in polar solvent.Though also with reference to above-mentioned condition, as polar solvent, water, methyl alcohol, ethanol, tetrahydrofuran (THF), dioxane etc. can be enumerated, these solvent can be used as required.Preferably water, methyl alcohol, ethanol, tetrahydrofuran (THF) etc. among these, particularly preferably water, methyl alcohol, ethanol etc.And very preferably by the situation that water and methanol mixed use, as the reaction soln after with the addition of alkali, water: the blending ratio of methyl alcohol is such as 1: 20 ~ 10: 1, is preferably the ratio of 1: 10 ~ 1: 1.

It should be noted that, the temperature of reaction of this alkaline hydrolysis can select such as room temperature to the proper temperature of the reflux temperature of solvent, as particularly preferred example, can enumerate the condition of 50 ~ 70 DEG C.Reaction times is generally 0.5 ~ 72 hour, be preferably 1 ~ 24 hour, more particularly, within the upper limit is preferably 24 hours, within being more preferably 20 hours, more preferably within 10 hours, lower limit is preferably more than 0.5 hour, be more preferably more than 1 hour, more preferably more than 3 hours, due to thin layer chromatography (TLC) can be utilized, high speed liquid chromatography (HPLC) etc. carrys out following response process, therefore usual at 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] productive rate of propionic acid suitable termination reaction when reaching maximum.

About add in the solution after basic hydrolysis under this alkaline condition acid, crystallization the content such as formation condition and acquisition method described above.

As example preferred in above-mentioned manufacture method, can be exemplified below.In the example of 3 kinds of manufacture method below, reaction times of the amount of the alkali used in alkaline hydrolysis, the temperature of reaction of hydrolysis reaction, hydrolysis reaction, add whipping temp before acid, the amount of acid of interpolation and the churning time of adding after acid and can adopt above-mentioned preference.

Relative to 1 equivalent 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] lower alkyl esters of propionic acid is under the sodium hydroxide of 1 ~ 3 equivalent or the existence of potassium hydroxide, at water, methyl alcohol, ethanol, in tetrahydrofuran (THF) or their mixed solvent, in 50 ~ 70 DEG C, this lower alkyl esters is reacted 1 ~ 24 hour, then, in the temperature of 10 ~ 50 DEG C, adding for a long time continuously relative to 1 equivalent alkali with methods such as droppings under stirring is the hydrochloric acid of 0.8 ~ 1.5 equivalent, sulfuric acid or phosphorus aqueous acid, further stirring 1 ~ 24 hour, obtain the method for crystallization.

And, relative to 1 equivalent 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] methyl ester of propionic acid or ethyl ester be under the existence of the sodium hydroxide of 1 ~ 2 equivalent, at water, methyl alcohol, in ethanol or their mixed solvent, in 50 ~ 70 DEG C, this methyl ester or ethyl ester are reacted 1 ~ 24 hour, then, in the temperature of 25 ~ 45 DEG C, be 0.5 ~ 2N aqueous hydrochloric acid of 0.9 ~ 1.2 equivalent relative to alkali with interpolation in 1 hour ~ 6 hours under stirring, further stirring 3 ~ 24 hours, obtain the method for crystallization.

In addition, at 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] to add relative to this methyl ester of 1 equivalent or ethyl ester in the methyl ester of propionic acid or ethyl ester be 0.5 ~ 2N aqueous sodium hydroxide solution and the methyl alcohol of 1 ~ 2 equivalent, in 50 ~ 70 DEG C of reactions after 1 ~ 24 hour, in the temperature of 25 ~ 45 DEG C, be 0.5 ~ 2N aqueous hydrochloric acid of 0.9 ~ 1.2 equivalent relative to 1 equivalent alkali with interpolation in 1 hour ~ 6 hours under stirring, further stirring 3 ~ 24 hours, obtains the method for crystallization.

[manufacture method of the Type B crystallization of this case compound 1]

As the manufacture method of the Type B crystallization of this case compound 1, following method can be enumerated: be dissolved in by this case compound 1 in any one or the two or more solvents in the group being selected from and being made up of acetone, methylene dichloride, methyl alcohol, ethyl acetate, methyl alcohol/acetic acid mixture and acetonitrile, make this case compound 1 crystallization by the solution dissolved.

As mentioned above, this case compound 1 can be prepared according to the method etc. of International Publication WO No. 03/70686 publication.

Further, as the solvent of above-mentioned use, acetone, methylene dichloride, methyl alcohol, ethyl acetate, acetonitrile, tetrahydrofuran (THF), diisopropyl ether, oil of mirbane, 2 can be enumerated, 2,2-trifluoroethanol, DMF, N, N-N,N-DIMETHYLACETAMIDE etc., and also can mix the use of these solvents.And then tetrahydrofuran (THF)/water, DMF/water, N,N-dimethylacetamide/water, tetrahydrofuran (THF)/methyl alcohol, diisopropyl ether/acetic acid, methyl alcohol/acetic acid etc. can be enumerated.Preferred acetone, methylene dichloride, methyl alcohol, ethyl acetate, acetonitrile, methyl alcohol/acetic acid etc. among these, particularly preferably acetone, methylene dichloride etc.

By in compound dissolution to solvent time, the consideration such as from the aspect of the productive rate of obtained crystallization, heats at the temperature preferably below the boiling point of solvent, and, when there is insolubles, wait operation removing insolubles preferably by filtration.

The difference of the ratio of solvent when kind, mixed solvent also according to used solvent of the amount of the solvent added and different, the amount of the solvent added is preferably the amount of the temperature compound dissolving below the boiling point of used solvent, and then, the consideration such as from the aspect of the productive rate of obtained crystallization, compound dissolution near the boiling point that the solvent added particularly preferably is used in solvent the amount of the concentration that reaches capacity.Specifically, such as, when using acetone as solvent, relative to 1g compound preferably 15 ~ 25ml, more preferably about 15ml.Further, when using methylene dichloride, relative to the amount of the preferred 30 ~ 50ml of 1g compound, preferred about 30ml further.

As the method for the solution cooling by heating the compound be prepared from, can enumerate cool rapidly, periodically method, the method preferably periodically cooled or the method for naturally cooling such as cooling, naturally cooling.

The difference of the ratio of solvent when kind, the mixed solvent of cooling temperature both according to the amount of solvent used, solvent used and different, also different from the difference of temperature during dissolved compound, temperature when being preferably cooled to compound to reach capacity more than concentration.

Cooling operation can under agitation carry out, also can carry out under static condition, from the viewpoint of accelerate crystallization precipitation, shorten the operating time, preferably under agitation carry out cooling operation.

It should be noted that, when utilizing aforesaid method to generate crystallization, adding a small amount of B crystallization as crystal seed is also preferred mode.

Usually by filtering the crystallization gathering precipitation.Further, gather after crystallization by filtering, can utilize for the solvent of dissolved compound or not obvious dissolving crystallized solvent or their mixed solution to clean crystallization, this is effective as going deimpurity operation.

The crystallization obtained can utilize the drying means (such as drying under reduced pressure, heating under reduced pressure is dry, normal heating is dry, air-dry) usually carried out to come dry.

As example preferred among above-mentioned manufacture method, following example can be enumerated.

In 1g this case compound 1, add the acetone of 15 ~ 25ml or the methylene dichloride of 30 ~ 50ml, be heated near boiling point, dissolve this compound, filter insolubles if desired, then at room temperature stir, a few hours ~ a few days after obtain the method for generated crystallization.

And, as other manufacture method of the Type B crystallization about this case compound 1, following method can also be enumerated: acid added in the solution under the alkaline condition of this case compound 1, in the process, before this case compound 1 is about to start crystallization, add the Type B crystallization of this case compound 1 as crystal seed, generate the Type B crystallization of this case compound 1, then obtain this crystallization.

Identical with the explanation in above-mentioned " manufacture method of the A type crystallization of this case compound 1 " one for this case compound 1 of the present invention, its shape, preparation method.Further, the preparation method of the solution under the alkaline condition of this case compound 1 waits also same as described above.In addition, solution under above-mentioned alkaline condition can be 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] alkaline hydrolysate of lower alkyl esters of propionic acid, this point is also same as described above.

The kind of the above-mentioned alkali for the preparation of the solution under alkaline condition and addition etc., for the kind of solvent that compound is dissolved together with alkali and addition etc. and the kind of acid of adding and addition, addition means, interpolation speed, add time temperature etc. also can according to above-mentioned explanation.As the method for the crystal seed of interpolation Type B crystallization, in mixed solution, preferably there is not the state of crystallization in the stage of adding crystal seed, and the state that the crystal seed after preferably adding exists in undissolved mode.Add acid after the alkali adding more than the equivalent of this compound dissolves, in this case, from the viewpoint of the dissolving avoiding crystal seed, the alkali preferably more than equivalent by added acid and after stage add the crystal seed of Type B crystallization.Further, now, use and to confirm in the alkali of more than equivalent based on machines such as pH meters and situation is also preferred method.That is, when use relative to this compound be the alkali of 1.5 equivalents to dissolve this compound, following method can be enumerated as preference: add the acid being equivalent to 0.5 equivalent, in the weakly alkaline stage of the pH display about 7 ~ 9 in system, add crystal seed.Further, preferably crystal seed is being added by adding before acid generates crystallization.When adding the hydrochloric acid of 2N with 1 hour ~ 6 hours, after the neutralization of the alkali more than the equivalent of this above-mentioned compound terminates, in the acid by interpolation 0.1 ~ 0.2 equivalent, the pH in system was shown in the weakly acidic stage probably to start to generate crystallization, therefore the preferred crystal seed adding Type B in the stage early than this.

The amount of added Type B crystallization is not particularly limited, as long as the addition of Type B crystallization is the undissolved amount of crystallization after adding, can enumerate usually add more than 0.01% relative to this compound, preferably more than 0.05%, particularly preferably add about 0.1%.And the upper limit is not particularly limited, can enumerate usually add less than 2% relative to this compound, preferably less than 1.5%, further preferably less than 1.0%, particularly preferably less than 0.3%.About the crystallization of separating out acquisition method, collect crystallization drying means, add the precipitation concentration etc. of the final compound after acid, can adopt and above-mentioned " manufacture method of the A type crystallization of this case compound 1 " identical condition.

As example preferred among above-mentioned manufacture method, following example can be enumerated.In the example of 3 kinds of following manufacture method, the amount of the alkali used, add whipping temp before acid, the amount of acid of interpolation, the amount of the crystal seed of the Type B of interpolation and the churning time of adding after acid and can adopt above-mentioned preference.

The sodium hydroxide of 0.8 ~ 3.0 equivalent or the water of potassium hydroxide is being contained relative to 1 equivalent this case compound 1, methyl alcohol, ethanol, dissolve this case compound 1 in tetrahydrofuran (THF) or their mixed solvent and obtain solution, in the temperature of 10 ~ 50 DEG C, adding in obtained solution for a long time relative to 1 equivalent alkali continuously with methods such as droppings under stirring is the hydrochloric acid of 0.8 ~ 1.5 equivalent, sulfuric acid or phosphorus aqueous acid, after weakly alkaline stage that pH in the process in system demonstrates 7 ~ 9 adds and is the Type B crystal seed of 0.01% ~ 2% relative to this compound, further stirring 1 ~ 24 hour, obtain the method for crystallization.

In addition, dissolve this case compound 1 in relative to the water of the sodium hydroxide of 1 equivalent this case compound 1 containing 0.9 ~ 2.0 equivalent, methyl alcohol, ethanol or their mixed solvent and obtain solution, in the temperature of 25 ~ 45 DEG C, stirring lower is 0.5 ~ 2N aqueous hydrochloric acid of 0.9 ~ 1.2 equivalent with within 1 hour ~ 6 hours, to add relative to 1 equivalent alkali in obtained solution, after weakly alkaline stage that pH in the process in system demonstrates 7 ~ 9 adds and is the Type B crystal seed of 0.05% ~ 1.5% relative to this compound, further stirring 1 ~ 5 hour, obtains the method for crystallization.

In addition, 0.5 ~ 2N aqueous sodium hydroxide solution and the methyl alcohol of 0.9 ~ 2.0 equivalent is added in 1 equivalent this case compound 1, be dissolved into solution, in the temperature of 25 ~ 45 DEG C, stirring lower is 0.5 ~ 2N aqueous hydrochloric acid of 0.9 ~ 1.2 equivalent with within 1 hour ~ 6 hours, to add relative to 1 equivalent alkali in above-mentioned solution, weakly alkaline stage that pH in the process in system demonstrates 7 ~ 9 stirs 1 ~ 5 hour further, obtains the method for crystallization after adding and being the Type B crystal seed of 0.1% relative to this compound.

Further, as the preference of manufacture method, following mode can also be enumerated.In the example of 3 kinds of manufacture method below, reaction times, whipping temp, the amount of acid of interpolation, the amount of the Type B crystal seed of interpolation and the churning time of adding after acid of adding before acid of the amount of the alkali used in alkaline hydrolysis, the temperature of reaction of hydrolysis reaction, hydrolysis reaction can adopt above-mentioned preference.

Relative to 1 equivalent 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] lower alkyl esters of propionic acid is under the sodium hydroxide of 1 ~ 3 equivalent or the existence of potassium hydroxide, at water, methyl alcohol, ethanol, in tetrahydrofuran (THF) or their mixed solvent, in 50 ~ 70 DEG C, this lower alkyl esters is reacted 1 ~ 24 hour, then, in the temperature of 10 ~ 50 DEG C, adding for a long time continuously relative to 1 equivalent alkali with methods such as droppings under stirring is the hydrochloric acid of 0.8 ~ 1.5 equivalent, sulfuric acid or phosphorus aqueous acid, after weakly alkaline stage that pH in the process in system demonstrates 7 ~ 9 adds and is the Type B crystal seed of 0.01% ~ 2% relative to this compound, further stirring 1 ~ 24 hour, obtain the method for crystallization.

And, relative to 1 equivalent 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] methyl ester of propionic acid or ethyl ester be under the existence of the sodium hydroxide of 1 ~ 2 equivalent, at water, methyl alcohol, in ethanol or their mixed solvent, in 50 ~ 70 DEG C, this methyl ester or ethyl ester are reacted 1 ~ 24 hour, then, in the temperature of 25 ~ 45 DEG C, be 0.5 ~ 2N aqueous hydrochloric acid of 0.9 ~ 1.2 equivalent relative to alkali with interpolation in 1 hour ~ 6 hours under stirring, after weakly alkaline stage that pH in the process in system demonstrates 7 ~ 9 adds and is the Type B crystal seed of 0.05% ~ 1.5% relative to this compound, further stirring 3 ~ 24 hours, obtain the method for crystallization.

In addition, at 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] to add relative to this methyl ester of 1 equivalent or ethyl ester in the methyl ester of propionic acid or ethyl ester be 0.5 ~ 2N aqueous sodium hydroxide solution and the methyl alcohol of 1 ~ 2 equivalent, in 50 ~ 70 DEG C of reactions after 1 ~ 24 hour, in the temperature of 25 ~ 45 DEG C, be 0.5 ~ 2N aqueous hydrochloric acid of 0.9 ~ 1.2 equivalent relative to 1 equivalent alkali with interpolation in 1 hour ~ 6 hours under stirring, after weakly alkaline stage that pH in the process in system shows 7 ~ 9 adds and is the Type B crystal seed of 0.1% relative to this compound, further stirring 3 ~ 24 hours, obtain the method for crystallization.

[manufacture method of the crystallization of this case compound 2]

In addition, about the crystallization of this case compound 2 of the present invention, advantage in formulation operation is larger, such as be easy to make the content of this case compound in each preparation even, etc., and, compared with the situation of oily matter, this crystallization is easily except being also favourable in desolventizing etc., in addition, owing to having found the manufacture method of this crystallization, it has had the advantage without the need to carrying out can obtaining with the refining of column chromatography enforcement in above-mentioned known production method this case compound of purity excellence, also being suitable for plant-scale manufacture, is very preferred.

As the manufacture method of the crystallization of this case compound 2, following method can be enumerated: be dissolved in by this case compound 2 in the good solvent being easy to dissolve and prepare solution, add in prepared solution and be difficult to the poor solvent dissolving this compound, generate the crystallization be made up of this compound, then obtain this crystallization.It should be noted that, this case compound 2 can be prepared according to the method for International Publication WO No. 03/70686 publication.

As the good solvent for dissolving this compound, toluene, ethyl acetate, tetrahydrofuran (THF), acetone, glycol dimethyl ether, methyl alcohol etc. can be enumerated, preferred acetone, toluene, tetrahydrofuran (THF) etc., particularly preferably acetone.And, the poor solvent added as the crystallization for generating this compound, heptane, diisopropyl ether, Virahol, t-butyl methyl ether, water etc. can be enumerated, use acetone preferably to use water as when good solvent, use toluene or tetrahydrofuran (THF) preferably to use heptane as when good solvent.As particularly preferred example, can enumerate and use acetone to make good solvent, make to use water as the combination of poor solvent.

The concentration of the solution prepared as utilizing good solvent, the upper limit is preferably below 20w/v%, is more preferably below 10w/v%, and lower limit is preferably more than 5w/v%.As the amount of added poor solvent, relative to good solvent, the upper limit is preferably below 2.0 times amount, is more preferably below 1.5 times amount, more preferably below 1.1 times amount, lower limit is preferably more than 0.8 times amount, is more preferably more than 0.9 times amount.Particularly preferably add 1.0 times amount.Also other modes of particularly preferably adding 1.05 times amount are had.As the additive process of poor solvent, preferably with the method that the methods such as dropping are added continuously for a long time.Preferably stir when adding poor solvent.Interpolation speed is different from the difference of the kind of the concentration of compound in the amount of used compound, solution, the good solvent used, poor solvent, when adding water as poor solvent in the acetone soln of compound, can enumerate and add the method for water with time of 1 hour ~ 3 hours.

For temperature during interpolation poor solvent, the upper limit is preferably less than 50 DEG C, is more preferably less than 40 DEG C, and more preferably less than 30 DEG C, lower limit is preferably more than 0 DEG C, is more preferably more than 10 DEG C, more preferably more than 20 DEG C.

When obtaining the crystallization generated, can enumerate 1 hour ~ 24 hours usually after adding poor solvent, preferably within 1 hour ~ 5 hours, carry out the acquisition of crystallization.

As gathering the method for crystallization separated out, filtrations can be utilized, incline and the known method such as to strain to obtain crystallization, preferably filtration usually.Further, after collecting crystallization by filtration, polar solvent (such as water, acetone or their mixed solution) can be utilized to clean crystallization, and it is effective as going deimpurity operation.

The crystallization obtained can utilize the drying means (such as drying under reduced pressure, heating under reduced pressure is dry, normal heating is dry, air-dry) usually carried out to come dry.

[manufacture method of the crystallization of this case compound 3]

In addition, about the crystallization of this case compound 3 of the present invention, advantage in formulation operation is larger, such as be easy to make the content of this case compound in each preparation even, etc., and, compared with the situation of oily matter, this crystallization is easily except being also favourable in desolventizing etc., in addition, owing to having found the manufacture method of this crystallization, it has had the advantage without the need to carrying out can obtaining with the refining of column chromatography enforcement in above-mentioned known production method this case compound of purity excellence, also being suitable for plant-scale manufacture, is very preferred.

As the manufacture method of the crystallization of this case compound 3, following method can be enumerated: be dissolved in by this case compound 3 in the good solvent being easy to dissolve and prepare solution, add in prepared solution and be difficult to the poor solvent dissolving this compound, generate the crystallization be made up of this compound, then obtain this crystallization.

It should be noted that, this case compound 3 can be prepared according to the method for International Publication WO No. 03/70686 publication.And, also can utilize and make 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid in such as methanol solvate, under acidic conditions, carry out the common methyl-esterified reaction such as methyl-esterified to be prepared.

As the good solvent for dissolving this compound, toluene, ethyl acetate, tetrahydrofuran (THF), acetone etc. can be enumerated, preferred acetone, tetrahydrofuran (THF) etc., particularly preferably tetrahydrofuran (THF).Further, as poor solvent, heptane, Virahol, methyl alcohol, water etc. can be enumerated, use acetone preferably to use water or heptane as when good solvent, use tetrahydrofuran (THF) preferably to use heptane, Virahol, water as when good solvent.As particularly preferred example, can enumerate and use tetrahydrofuran (THF) as good solvent, use water as the combination of poor solvent.

The concentration of the solution prepared as utilizing good solvent, the upper limit is preferably below 20w/v%, is more preferably below 10w/v%, and lower limit is preferably more than 5w/v%.As the amount of added poor solvent, relative to good solvent, the upper limit is preferably below 2.0 times amount, is more preferably below 1.5 times amount, more preferably below 1.1 times amount, lower limit is preferably more than 0.8 times amount, is more preferably more than 0.9 times amount.Particularly preferably add 1.0 times amount.Also other modes of particularly preferably adding 1.05 times amount are had.As the additive process of poor solvent, preferably with the method that the methods such as dropping are added continuously for a long time.Preferably stir when adding poor solvent.Interpolation speed is different from the difference of the kind of the concentration of compound in the amount of used compound, solution, the good solvent used, poor solvent, when adding water as poor solvent in the tetrahydrofuran solution of compound, the method for adding with time of 1 hour ~ 3 hours can be enumerated.

About temperature during interpolation poor solvent, the upper limit is preferably less than 50 DEG C, is more preferably less than 40 DEG C, and more preferably less than 35 DEG C, lower limit is preferably more than 0 DEG C, is more preferably more than 10 DEG C, more preferably more than 25 DEG C.

When obtaining the crystallization generated, can enumerate usually after adding poor solvent in the ice-cooled lower acquisition through 1 hour ~ 24 hours, preferably 1 hour ~ carry out for 5 hours crystallization.

As gathering the method for crystallization separated out, filtrations can be utilized, incline and the known method such as to strain to obtain crystallization, preferably filtration usually.Further, after collecting crystallization by filtration, polar solvent (such as water, acetone or their mixed solution) can be utilized to clean crystallization, and it is effective as going deimpurity operation.

The crystallization obtained can utilize the drying means (such as drying under reduced pressure, heating under reduced pressure is dry, normal heating is dry, air-dry) usually carried out to come dry.

This case compound can suppress the struvite edema of mouse, supersensitivity edema, acetic acid twisting to react and rat assist agent arthritis with the oral administration of 0.1 ~ 500mg/kg, even if within 3 days, also had no dead example with 500mg/kg/ days to Mouse oral administration in addition, therefore be safe compound as the medicine being used for Mammals (pet such as preferred people, dog and cat or companion animals or domestic animal), the activeconstituents as medicine is useful material.As the medicine for Mammals (pet such as preferred people, dog and cat or companion animals or domestic animal), that can enumerate the state be confirmed for the various acute or chronic inflammatory reaction caused by the generation due to prostaglandin(PG) and/or leukotriene, various disease or morbid state (i.e. diseases associated with inflammation, anaphylactic disease, autoimmune disease, pain) prevents and/or treats any one in medicine as preference.

When this case compound is used as above-mentioned medicine, directly uses this case compound of significant quantity or be mixed and made into pharmaceutical composition with pharmaceutically useful carrier, as this carrier, also can use suspension agent or other known carriers such as such as carboxymethyl cellulose.Give one example, the method used in the pure water be suspended in by the compounds of this invention containing 0.5% carboxymethyl cellulose can be enumerated.

As the formulation agent shape for aforementioned pharmaceutical compositions, can enumerate tablet, powder, granule, syrup, suspension agent, capsule, injection etc., consider the character of the crystallization of this case compound, particularly preferably pharmaceutical composition is drying agent.In order to carry out this manufacture, the various carriers of these preparations corresponding can be used.Such as, as the carrier of oral preparation, vehicle, tackiness agent, lubricant, flow promoting agent, tinting material can be enumerated.

When the compounds of this invention being made parenteral dose of injection etc., as thinner, generally use distilled water for injection, physiological saline, D/W, injection vegetables oil, propylene glycol, polyoxyethylene glycol etc.And then, also can add sterilant, sanitas, stablizer, isotonic agent, painless agent etc. as required.

When the compounds of this invention is carried out administration to mammals (such as people), can with the form oral administration of tablet, powder, granule, suspension agent, capsule, in addition, also can with the non-oral administration of form of injection (comprising drop) and suppository, gelifying agent, lotion, ointment, ointment or sprays.Its dosage is according to being suitable for disease, administering mode, age of patient, body weight, the difference of degree etc. of symptom and different, and be such as generally grown up 1 ~ 1000mg every day, point 1 ~ 3 administration.Be generally during administration a few days ~ administration day after day of 2 months, but also can according to the symptom of patient, during the dosage of increase and decrease every day and administration.

Further, as the similar compound of this case compound, can enumerate following compound, these compounds also can manufacture according to the method for International Publication WO No. 03/70686 publication or manufacture method given this description.

3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1H-indazole-5-base) phenyl] propionic acid;

3-[3-amino-5-(1-ethyl-1H-indazole-5-base)-4-(1,2-indane-2-base oxygen base) phenyl] propionic acid;

3-[4-(1,2-indane-2-base oxygen base)-3-(N-methylamino)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid;

3-[4-(1,2-indane-2-base oxygen base)-5-(1H-indazole-5-base)-3-(N-methylamino) phenyl] propionic acid;

3-[5-(1-ethyl-1H-indazole-5-base)-4-(1,2-indane-2-base oxygen base)-3-(N-methylamino) phenyl] propionic acid;

3-[3-amino-4-(fluoro-1, the 2-indane-2-base oxygen base of 4-)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(fluoro-1, the 2-indane-2-base oxygen base of 5-)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(fluoro-1, the 2-indane-2-base oxygen base of 5,6-bis-)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid;

3-[3-amino-4-(1-hydroxyl-1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(4-hydroxyl-1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(5-hydroxyl-1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(5,6-dihydroxyl-1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid;

3-[3-amino-4-(4-methoxyl group-1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(5-methoxyl group-1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(5,6-dimethoxy-1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid;

3-[3-amino-4-(4-benzyloxy-1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(4-benzyloxy-1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(5,6-benzyloxy-1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid;

3-[3-amino-4-(fluoro-1, the 2-indane-2-base oxygen base of 4-)-5-(1H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(fluoro-1, the 2-indane-2-base oxygen base of 5-)-5-(1H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(fluoro-1, the 2-indane-2-base oxygen base of 5,6-bis-)-5-(1H-indazole-5-base) phenyl] propionic acid;

3-[3-amino-4-(1-hydroxyl-1,2-indane-2-base oxygen base)-5-(1H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(4-hydroxyl-1,2-indane-2-base oxygen base)-5-(1H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(5-hydroxyl-1,2-indane-2-base oxygen base)-5-(1H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(5,6-dihydroxyl-1,2-indane-2-base oxygen base)-5-(1H-indazole-5-base) phenyl] propionic acid;

3-[3-amino-5-(1H-indazole-5-base)-4-(4-methoxyl group-1,2-indane-2-base oxygen base) phenyl] propionic acid and isomer thereof;

3-[3-amino-5-(1H-indazole-5-base)-4-(5-methoxyl group-1,2-indane-2-base oxygen base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(5,6-dimethoxy-1,2-indane-2-base oxygen base)-5-(-indazole-5-base) phenyl] propionic acid;

3-[3-amino-4-(4-benzyloxy-1,2-indane-2-base oxygen base)-5-(1H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(4-benzyloxy-1,2-indane-2-base oxygen base)-5-(1H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(5,6-benzyloxy-1,2-indane-2-base oxygen base)-5-(1H-indazole-5-base) phenyl] propionic acid;

3-[3-amino-5-(1-ethyl-1H-indazole-5-base)-4-(fluoro-1, the 2-indane-2-base oxygen base of 4-) phenyl] propionic acid and isomer thereof;

3-[3-amino-5-(1-ethyl-1H-indazole-5-base)-4-(fluoro-1, the 2-indane-2-base oxygen base of 5-) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(fluoro-1, the 2-indane-2-base oxygen base of 5,6-bis-)-5-(1-ethyl-1H-indazole-5-base) phenyl] propionic acid;

3-[3-amino-5-(1-ethyl-1H-indazole-5-base)-4-(1-hydroxyl-1,2-indane-2-base oxygen base) phenyl] propionic acid and isomer thereof;

3-[3-amino-5-(1-ethyl-1H-indazole-5-base)-4-(4-hydroxyl-1,2-indane-2-base oxygen base) phenyl] propionic acid and isomer thereof;

3-[3-amino-5-(1-ethyl-1H-indazole-5-base)-4-(5-hydroxyl-1,2-indane-2-base oxygen base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(5,6-dihydroxyl-1,2-indane-2-base oxygen base)-5-(1-ethyl-1H-indazole-5-base) phenyl] propionic acid;

3-[3-amino-5-(1-ethyl-1H-indazole-5-base)-4-(4-methoxyl group-1,2-indane-2-base oxygen base) phenyl] propionic acid and isomer thereof;

3-[3-amino-5-(1-ethyl-1H-indazole-5-base)-4-(5-methoxyl group-1,2-indane-2-base oxygen base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(5,6-dimethoxy-1,2-indane-2-base oxygen base)-5-(1-ethyl-1H-indazole-5-base) phenyl] propionic acid;

3-[3-amino-4-(4-benzyloxy-1,2-indane-2-base oxygen base)-5-(1-ethyl-1H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(4-benzyloxy-1,2-indane-2-base oxygen base)-5-(1-ethyl-1H-indazole-5-base) phenyl] propionic acid and isomer thereof;

3-[3-amino-4-(5,6-benzyloxy-1,2-indane-2-base oxygen base)-5-(1-ethyl-1H-indazole-5-base) phenyl] propionic acid.

Embodiment

Provide embodiment, test example below, in further detail the present invention is described, but the present invention is not limited to these.

(embodiment 1)

The preparation example 1 of the crystallization of 3-[4-(1,2-indane-2-base oxygen base)-3-(1-methyl isophthalic acid H-indazole-5-base)-5-nitrophenyl] methyl propionate (this case compound 2)

At 3-[the bromo-4-(1 of 3-, 2-indane-2-base oxygen base)-5-nitrophenyl] methyl propionate (14.00g, prepare according to the method for International Publication WO No. 03/70686 publication), 1-methyl isophthalic acid H-indazole-5-boric acid (7.62g, prepare according to the method for International Publication WO No. 03/70686 publication), acid chloride (75mg, manufacture with Guang Chun medicine society), triphenylphosphine (0.17g, with Guang Chun medicine society manufacture) in add THF (40ml), after stirring, be added in water (27ml) and be dissolved with Tripotassium phosphate (16.97g, with Guang Chun medicine society manufacture) solution, nitrogen replacement is carried out in system.Then, stir this mixed solution in 60 DEG C to react for 4 hours.Confirm after reaction terminates, carry out separatory, obtain upper strata, after upper strata is cooled to room temperature, add ethyl acetate (40ml) and gac (manufacture of 2.8g, Japanese Environment chemistry society), in stirring at room temperature 1 hour.Filtering suspension liquid obtains filtrate, and then with the residue in ethyl acetate (20ml) filter rinsed, obtains washing lotion, filtrate and washing lotion is merged, carries out concentrating under reduced pressure, obtain concentrated solution (44g).Then in concentrated solution, add acetone (140ml), after stirring, in room temperature, stir lower interpolation water (140ml) in 1 hour, further in stirring at room temperature 1 hour.Then, filter this mixed solution, and then with the solid matter in water (70ml) filter rinsed, obtain wet solid matter.In 50 DEG C, drying under reduced pressure is carried out to this wet solid matter, thus obtain the crystallization of title compound (15.7g).

(embodiment 1-A, B)

The preparation example 2 of the crystallization of this case compound 2

For obtaining the later operation of concentrated solution in embodiment 1, using toluene to replace acetone, using heptane to replace water, thus the crystallization of this compound can be obtained.

Further, replacing the acetone of embodiment 1 by using tetrahydrofuran (THF), using heptane to replace water, the crystallization of this case compound 2 can be obtained.

(embodiment 2)

The preparation example 1 of 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] methyl propionate (this case compound 3)

Add THF (138ml), stabilization nickel ((stabilization ニ Star ケ Le) 4.42g, wave chemical society day manufacture), water (4ml) in this case compound 2 (13.0g) prepared according to embodiment 1, after stirring, carry out hydrogen exchange in system, within 7 hours, react in 50 DEG C of stirrings under a hydrogen atmosphere.After confirming that reaction terminates, nitrogen replacement is carried out to this reaction solution, after filtration, obtains filtrate, and then with the residue in THF (34ml) filter rinsed, obtain washing lotion.Merging filtrate and washing lotion, added gac (2.6g, Japanese Environment chemistry society manufacture) in the solution after merging, in stirring at room temperature 1 hour.Filtering suspension liquid obtains filtrate, then uses the residue in THF (34ml) filter rinsed, obtains washing lotion.At this, filtrate obtained and washing lotion are merged, in room temperature solution after merging, added water (207ml) with 1 hour, and then stir 1 hour under ice-cooling.Then, filter this mixed solution, and then with the solid matter in water (68ml) filter rinsed, obtain wet solid matter.In 50 DEG C, drying under reduced pressure is carried out to this wet solid matter, thus obtain the crystallization of title compound (10.3g).

(embodiment 2-A, B)

The preparation example 2 of this case compound 3

Use heptane substitutes the water in the mixed solution being added on filtrate and washing lotion in example 2, thus can obtain the crystallization of this case compound 3.

Further, by using Virahol as this solvent, the crystallization of this case compound 3 can be obtained.

(embodiment 3)

The preparation example 1 of the A type crystallization of this case compound 1

Add methyl alcohol (45ml) in this case compound 3 (10.0g) obtained in example 2, add 2N aqueous sodium hydroxide solution (17.0ml) after stirring, under stirring, carry out alkaline hydrolysis in 3 hours in 60 DEG C.After reaction, reaction solution is cooled to 35 DEG C, added 2N aqueous hydrochloric acid (17.0ml) with 2 hours, and then stir 16 hours in 35 DEG C.Then, filter this mixed solution, and then with water (27ml) and the solid matter in the mixed solution filter rinsed of methyl alcohol (13ml), obtain wet solid matter.In 50 DEG C, drying under reduced pressure is carried out to this wet solid matter, obtain the crystallization of 9.2g.

(embodiment 4)

The preparation example 1 of the Type B crystallization of this case compound 1

In the A type crystallization (1.0g) of this case compound 1 prepared according to embodiment 3, add acetone (17ml), in the water-bath of 60 DEG C, heating makes it dissolve.Then at room temperature stirred solution all night.Filter the throw out generated, obtain solid on the filter.Then carry out drying under reduced pressure at 50 DEG C, thus obtain the crystallization of 0.55g.

(embodiment 5)

The preparation example 2 of the Type B crystallization of this case compound 1

In the A type crystallization (1.0g) of this case compound 1 prepared according to embodiment 3, add methylene dichloride (31ml), in the water-bath of 40 DEG C, heating makes it dissolve.Then at room temperature stirred solution all night.Filter the throw out generated, obtain solid on the filter.Then carry out drying under reduced pressure at 50 DEG C, thus obtain the crystallization of 0.81g.

This crystallization demonstrates the spectrum identical in fact with Fig. 7 by the Differential Scanning Calorimeter analysis of test example 4 described later, confirms the Type B crystallization that this crystallization is this case compound 1.

(embodiment 6)

The preparation example 3 of the Type B crystallization of this case compound 1

In the A type crystallization (10.0g) of this case compound 1 prepared according to embodiment 3, add methyl alcohol (45ml), after stirring, add 2N aqueous sodium hydroxide solution (17.0ml), stir 1 hour in 60 DEG C.This mixed solution is cooled to 35 DEG C, 2N aqueous hydrochloric acid (7.0ml) is added with 30 minutes, the pH confirming mixed solution is after 7 ~ 9, adds rapidly the crystal seed (0.1g) of the Type B crystallization of this case compound 1 prepared according to embodiment 4, stirs 10 minutes.Then in this mixed solution, added 2N aqueous hydrochloric acid (10.0ml) with 1 hour, and then stir 2 hours in 35 DEG C.Then filter this mixed solution, and then with water (27ml) and the solid matter in the mixed solution filter rinsed of methyl alcohol (13ml), obtain wet solid matter.In 50 DEG C, drying under reduced pressure is carried out to this wet solid matter, thus obtain the white crystals of 9.7g.

This crystallization is measured by the powder x-ray diffraction of test example 3 described later and demonstrates the spectrum identical in fact with Fig. 6, confirms the Type B crystallization that this crystallization is this case compound 1.Further, this crystallization demonstrates the spectrum identical in fact with Fig. 7 by the Differential Scanning Calorimeter analysis of test example 4 described later, and confirming it is Type B crystallization.

(embodiment 7)

The preparation example 4 of the Type B crystallization of this case compound 1

Utilizing interpolation methyl alcohol (360.0ml) in this case compound 3 (80.0g) obtained based on the method for embodiment 2, add water (36.2ml) and 2N aqueous sodium hydroxide solution (99.7ml) after stirring, under stirring, carry out alkaline hydrolysis in 3 hours in 60 DEG C.After reaction, filter out the insolubless such as the dust in reaction solution, after add water (180.2ml), be adjusted to 35 DEG C.Add 2N aqueous hydrochloric acid (10.7ml) with 8 points of clockwise mixed solutions, the pH confirming mixed solution is after 7.9, adds rapidly the crystal seed (0.08g) of the Type B crystallization of this case compound 1 prepared according to embodiment 4, stirs 4 minutes.Then in this mixed solution, added 2N aqueous hydrochloric acid (89.0ml) with 111 minutes, and then stir 14.3 hours in 35 DEG C.Then filter this mixed solution, with the solid matter in the mixed solution filter rinsed of water (213.4ml) and methyl alcohol (106.7ml), obtain wet solid matter.In this wet solid matter, add water (213.4ml) and methyl alcohol (106.7ml), again make mixed solution, stir 37 minutes in 18 ~ 20 DEG C.Then, filter this mixed solution, and then with the solid matter in the mixed solution filter rinsed of water (21.3ml) and methyl alcohol (10.7ml), obtain wet solid matter.In 50 DEG C, drying under reduced pressure is carried out to this wet solid matter, thus obtain the white crystals of 76.28g.

This crystallization demonstrates the spectrum identical in fact with Fig. 7 by the Differential Scanning Calorimeter analysis of test example 4 described later, confirms the Type B crystallization that this crystallization is this case compound 1.

(embodiment 8)

The preparation example 1 of the mixed crystallization of this case compound 1

The Type B crystallized mixed that the A type crystallization of this case compound 1 using mortar and pestle to be prepared according to embodiment 3 by 0.9g and 0.1g are prepared according to embodiment 4, obtains the mixture of A type crystallization 90% and Type B crystallization 10%.

(embodiment 9)

The preparation example 2 of the mixed crystallization of this case compound 1

The Type B crystallized mixed that the A type crystallization of this case compound 1 using mortar and pestle to be prepared according to embodiment 3 by 0.1g and 0.9g are prepared according to embodiment 4, obtains the mixture of A type crystallization 10% and Type B crystallization 90%.

(embodiment 10)

The preparation example 2 of the A type crystallization of this case compound 1

This case compound 3 (3.92kg) method according to embodiment 2 obtained is put in reaction unit A (model: BD-1,30L lift reaction unit, Asahi Techno Glass Co., Ltd. manufacture), add methyl alcohol (14.08kg) wherein, stir.After adding 2N aqueous sodium hydroxide solution (6.76kg), be heated to 60.6 DEG C with 27 minutes.After stirring 4 hours 9 minutes in about 60 DEG C, be cooled to 35 DEG C with 19 minutes, use film filter filtering reacting liquid, preparation feedback liquid 1.And then, this case compound 3 (3.92kg) obtained according to embodiment 2 is put in reaction unit A, adds methyl alcohol (14.25kg) wherein, stir.After adding 2N aqueous sodium hydroxide solution (6.70kg), be heated to 60.0 DEG C with 30 minutes.After stirring 4 hours 30 minutes in about 60 DEG C, 34.6 DEG C are cooled to 17 minutes, use film filter filtering reacting liquid, merge with reaction solution 1 in reaction unit B (model: BD-2,100L lift reaction unit, AsahiTechno Glass Co., Ltd. manufacture), be prepared into reaction solution 2.This reaction solution 2 is remained on 30 ~ 35 DEG C, and stir lower dropping 2N aqueous hydrochloric acid (13.30kg) in 5 hours 48 minutes, crystallization, is prepared into partial crystallization liquid.And then, this partial crystallization liquid is maintained at about 35 DEG C, stirs 10 hours 5 minutes simultaneously, then drop in strainer (model: F-9, φ 600mm vacuum filter, ASAHI ENGINEERING Co., Ltd. manufacture), filtered by suction, obtain wet crystallization.The mixed solution of water (20.00kg) and methyl alcohol (7.88kg) is sprinkled upon in the wet crystallization on this strainer, aspirates, to clean wet crystallization.Continue again to aspirate, fully dewater, obtain the wet crystallization (15.571kg) of the A type crystallization of this case compound 1.Now, be 1 hour 5 minutes by partial crystallization liquid by filtering the time obtained needed for wet crystallization, the time needed for cleaning the wet crystallization on strainer with the mixed solution of water and methyl alcohol is 1 hour 44 minutes, and the time needed for dehydration is 50 minutes.This wet crystallization is layered on dish, put into drying machine (model: BM-6, flaggy formula Vacuumdrier, VAC-300PR, Espec Co., Ltd. manufacture), carry out the drying under reduced pressure of 3 days (consuming time 65 hours 52 minutes) in 50 DEG C, obtain the A type crystallization (7.402kg) of this case compound 1.

This crystallization is measured by the powder x-ray diffraction of test example 3 described later and demonstrates the spectrum identical in fact with Fig. 3, confirms the A type crystallization that this crystallization is this case compound 1.Further, this crystallization demonstrates the spectrum identical in fact with Fig. 4 by the Differential Scanning Calorimeter analysis of test example 4 described later, confirms the A type crystallization that this crystallization is this case compound 1.

(embodiment 11)

The preparation example 5 of the Type B crystallization of this case compound 1

Put in reaction unit A (model: BD-1,30L lift reaction unit, Asahi Techno Glass Co., Ltd. manufacture) by utilizing this case compound 3 (3.90kg) obtained based on the method for embodiment 2, add methyl alcohol (13.75kg) wherein, stir.After adding 2N aqueous sodium hydroxide solution (5.20kg) and water (1.75kg), be heated to 60 DEG C with 42 minutes.After stirring 2 hours 29 minutes in about 60 DEG C, be cooled to 35.0 DEG C with 13 minutes, use film filter filtering reacting liquid, preparation feedback liquid 1.And then, this case compound 3 (3.90kg) obtained according to embodiment 2 is put in reaction unit A, adds methyl alcohol (13.97kg) wherein, stir.After adding 2N aqueous sodium hydroxide solution (5.20kg) and water (1.75kg), be heated to 60 DEG C with 40 minutes.After stirring 2 hours 34 minutes in about 60 DEG C, 35.0 DEG C are cooled to 19 minutes, use film filter filtering reacting liquid, merge with reaction solution 1 in reaction unit B (model: BD-2,100L lift reaction unit, Asahi Techno Glass Co., Ltd. manufacture), be prepared into reaction solution 2.Add water (17.36kg) in reaction solution 2 after, this solution is remained on 30 ~ 35 DEG C, stir lower dropping 2N aqueous hydrochloric acid (0.92kg) in 38 minutes, the moment reaching 7.90 at pH interrupts dripping.Then, after adding the Type B crystallization (7.795g) of this case compound 1, dripped 2N aqueous hydrochloric acid (9.08kg) with 3 hours 50 minutes, crystallization, is prepared into partial crystallization liquid.And then, this partial crystallization liquid is maintained at about 35 DEG C, stir after within 8 hours 42 minutes, stirring and drop in strainer (model: F-9, φ 600mm vacuum filter, ASAHI ENGINEERING Co., Ltd. manufacture), filtered by suction similarly to Example 10, obtain wet crystallization.The mixed solution of water (20.78kg) and methyl alcohol (8.10kg) is sprinkled upon in the wet crystallization obtained on this strainer, aspirates, to clean wet crystallization.And then continue to aspirate, fully dewater, obtain the wet crystallization of the Type B crystallization of this case compound 1.Now, be 8 minutes by partial crystallization liquid by filtering the time obtained needed for wet crystallization, the time needed for cleaning the wet crystallization on strainer with the mixed solution of water and methyl alcohol is 10 minutes, and the time needed for dehydration is 37 minutes.In order to improve the purity of this wet crystallization, dropped in the mixed solution of water (21.00kg) and methyl alcohol (8.18kg) and made suspension, stir after crystallization being cleaned in 34 minutes, dropped in strainer (model: F-9, φ 600mm vacuum filter, ASAHI ENGINEERING Co., Ltd. manufacture).Then, the mixed solution of water (2.10kg) and methyl alcohol (0.80kg) is dropped in strainer, filtered by suction, obtain wet crystallization, and then continue to aspirate, fully dewater, obtain the wet crystallization (12.211kg) of the Type B crystallization of this case compound 1.Now, be 4 minutes by filtering the time obtained needed for wet crystallization by suspension, the time needed for dehydration is 16 minutes.This wet crystallization is layered on dish, put into drying machine (model: BM-6, flaggy formula Vacuumdrier, VAC-300PR, Espec Co., Ltd. manufacture), carry out 3 days (consuming time 71 hours 3 minutes) drying under reduced pressure in 50 DEG C, obtain the Type B crystallization (7.412kg) of this case compound 1.

This crystallization is measured by the powder x-ray diffraction of test example 3 described later and demonstrates the spectrum identical in fact with Fig. 6, confirms the Type B crystallization that this crystallization is this case compound 1.Further, this crystallization demonstrates the spectrum identical in fact with Fig. 7 by the Differential Scanning Calorimeter analysis of test example 4 described later, confirms the Type B crystallization that this crystallization is this case compound 1.

(test example 1)

The mensuration 1 of filtration velocity

The mixed solution (blending ratio 1: 2) (50ml) of first alcohol and water is added in the A type crystallization (5.0g) of this case compound 1 prepared according to embodiment 3, after stirring 30 minutes in 25 DEG C, paulownia mountain funnel (paulownia Shan ロ ー ト) (internal diameter 40mm, paulownia mountain funnel with filter paper No.3) and suction unit is used to filter.Now, the filtrate obtaining 10ml needs 2 minutes 37 seconds, and the filtrate obtaining 20ml needs 7 minutes 45 seconds, and the filtrate obtaining 30ml needs 15 minutes 14 seconds, and final needs obtain the filtrate of 40ml for 25 minutes 24 seconds.Further, by carrying out drying under reduced pressure in 50 DEG C to the wet solid matter on funnel, the crystallization of 4.9g is obtained.

And, methyl alcohol is added: water (1: 2) mixed solution (50ml) in the Type B crystallization (5.0g) of this case compound 1 prepared according to embodiment 4, after stirring 30 minutes in 25 DEG C, paulownia mountain funnel (internal diameter 40mm, paulownia mountain funnel with filter paper No.3) and suction unit is used to filter.The filtrate obtaining 10ml needs 8 seconds, and the filtrate obtaining 20ml needs 17 seconds, and the filtrate obtaining 30ml needs 28 seconds, and final needs obtain the filtrate of 42ml for 2 minutes.Further, in 50 DEG C, drying under reduced pressure is carried out to the wet solid matter on funnel, obtain the crystallization of 4.7g.

As shown in above-mentioned example, the time sometimes obtained needed for Type B crystallization is in a ratio of less than 1/10th of the A type crystallization of equivalent with the time needed for the crystallization of A type obtaining roughly equivalent, thus can confirms the filterableness of Type B crystallization excellence of the present invention.

(test example 1-2)

The mensuration 2 of filtration velocity

The filterableness of the Type B crystallization of this case compound 1 in the filterableness of the A type crystallization of this case compound 1 in embodiment 10 and embodiment 11 is compared.For each crystallization, compare the time needed for following 3 stages, namely partial crystallization liquid drops in strainer and aspirates by (1), is separated into the time needed for wet crystallization and mother liquor; (2) then the mixed solution input of water and methyl alcohol is equipped with in the strainer of wet crystallization, aspirates, the time of the wet crystallization of cleaning; (3) last, continue suction, until fully reduce the time of the water ratio of the wet crystallization after cleaning, the crystallization of result A type is: (1) 1 hour 5 minutes, (2) 1 hours 44 minutes, (3) 50 minutes, on the other hand, Type B crystallization is: (1) 8 minute, (2) 10 minutes, (3) 37 minutes, can confirm the filterableness of Type B crystallization excellence of the present invention.

(test example 1-3)

The mensuration of the water ratio after filtration

Calculate the water ratio of each crystallization obtained in embodiment 10 and embodiment 11 according to the weight of wet crystallization and the weight of dry post crystallization, the crystallization of result A type is 52.5%, Type B crystallization is 39.3%, and the drying property that can confirm Type B crystallization of the present invention is also excellent.The results are shown in table 1.Although embodiment 10 and embodiment 11 are all dry 3 days, can easily infer, for the time in fact needed for drying and energy, the Type B crystallization that water ratio is low lower.

[table 1]

Table 1: measurement of water-content coefficient result

(test example 2)

Solubility test

The Type B crystallization of this case compound 1 that the A type crystallization of this case compound 1 prepared according to embodiment 3 by 10mg and 10mg are prepared according to embodiment 4 measures in 10mL centrifuge tube respectively, respective interpolation 3mL Japanese Pharmacopoeia slaking test liquid the 1st liquid (pH1.2), in 37 DEG C of vibrations 24 hours, filtering solution after vibration, accurate measuring 1mL filtrate, accurate interpolation 1mL acetonitrile, makes sample solution.

For sample solution, according to following HPLC condition, the standardized solution utilizing concentration known measures the concentration of sample solution, obtains solubleness.

Japanese Pharmacopoeia slaking test liquid the 2nd liquid (pH6.8) is tested similarly, obtains solubleness.

It the results are shown in table 3.

[table 2]

Condition

Injection volume: 10 μ L

Detector: ultraviolet light absorption photometer (measuring wavelength: 235nm)

Moving phase: 50mmol/L SODIUM PHOSPHATE, MONOBASIC/acetonitrile mixture (55: 45)

Post: YMC-Pack Pro C18 internal diameter is 4.6mm, length is 15cm (YMC manufacture)

Column temperature: 40 DEG C

Flow: 1.0mL/ minute

[table 3]

Table 3: solubility test result

As shown in table 3, in Japanese Pharmacopoeia slaking test liquid the 1st liquid (pH1.2) and Japanese Pharmacopoeia slaking test liquid the 2nd liquid (pH6.8), the solubleness of A type crystallization is 3 times of Type B crystallization, can confirm the high resolution of A type of the present invention crystallization.

(test example 3)

Powder x-ray diffraction

Powder x-ray diffraction is carried out for the crystallization obtained in each embodiment of present specification.

[table 4]

Condition determination

X-ray diffraction device: the XRD-6000 that Shimadzu Seisakusho Ltd. manufactures

X-ray source: CuK α (40kV30mA)

Scan pattern: continuously

Sweep velocity: 2 °/minute

Scanning interval: 0.02 °

Turntable driving axle: θ-2 θ

Sweep limit: 5 °-40 °

Scatter slit: 1 °

By optical slits: 0.30mm

The result of this mensuration is as follows.

Measure the crystallization of this case compound 2 obtained according to embodiment 1, result obtains the spectrum shown in Fig. 1.Confirming at 2 θ in the powder x-ray diffraction spectrum of the crystallization of this case compound 2 is 7.6 °, 15.3 °, 18.0 °, 21.3 ° and 26.9 ° of characteristic peaks located.Further, any place also in 16.3 °, 20.4 °, 23.0 ° or 30.5 ° or all confirm peak, the peak at any place among these 2 θ also can think it is at least characteristic peak.And then any place also in 11.5 °, 19.1 °, 25.1 ° or 25.8 ° or all confirm peak, the peak at any place among these 2 θ at least also can be considered to characteristic peak.This crystallization is also observed by the shape utilizing naked eyes to carry out and is judged as crystallization, also can confirm that it is crystallization really by above-mentioned analytical data.

Further, measure the crystallization of this case compound 3 obtained according to embodiment 2, result obtains the spectrum shown in Fig. 2.In the powder x-ray diffraction spectrum of the crystallization of this case compound 3, be that 8.6 °, 12.7 °, 17.2 °, 17.6 °, 18.9 ° and 21.0 ° of places confirm characteristic peak at 2 θ.Further, any place also in 14.7 °, 18.4 °, 19.4 ° or 22.1 ° or all confirm peak, the peak at any place among these 2 θ also can think it is at least characteristic peak.And then any place also in 11.9 °, 14.2 °, 23.0 °, 24.7 °, 26.1 °, 26.8 ° or 32.6 ° or all confirm peak, the peak at any place among these 2 θ also can think it is at least characteristic peak.This crystallization is also observed by the shape utilizing naked eyes to carry out and is judged as crystallization, also can confirm that it is crystallization really by above-mentioned analytical data.

Further, measure the A type crystallization of this case compound 1 obtained according to embodiment 3, result obtains the spectrum shown in Fig. 3.In the powder x-ray diffraction spectrum of the A type crystallization of this case compound 1, be that 6.9 °, 14.4 °, 16.4 °, 18.2 °, 25.0 ° and 27.5 ° of places confirm characteristic peak at 2 θ.Further, any place also in 20.0 °, 20.7 °, 22.9 ° or 25.4 ° or all confirm peak, the peak at any place among these 2 θ also can think it is at least characteristic peak.And then any place also in 10.2 °, 12.7 °, 15.0 ° or 23.8 ° or all confirm peak, the peak at any place among these 2 θ also can think it is at least characteristic peak.

Further, measure the Type B crystallization of this case compound 1 obtained according to embodiment 6, result obtains the spectrum shown in Fig. 6.In the powder x-ray diffraction spectrum of the Type B crystallization of this case compound 1, be that 14.4 °, 15.9 °, 17.3 °, 22.2 ° and 22.9 ° of places confirm characteristic peak at 2 θ.Further, any place also in 8.6 °, 9.8 °, 21.2 °, 23.6 ° or 28.4 ° or all confirm peak, the peak at any place among these 2 θ also can think it is at least characteristic peak.And then, any place also in 12.6 °, 18.0 °, 18.3 °, 18.8 °, 19.2 °, 19.8 °, 20.4 °, 25.3 °, 26.6 ° or 31.8 ° or all confirm peak, the peak at any place among these 2 θ also can think it is at least characteristic peak.

(test example 3-2)

The measuring method of crystallization purity

When incorporation rate when being mixed with the different crystal type of this case compound 1 is calculated, such as use collimated beam method optical system, measure with following condition, described collimated beam method optical system uses the spectrometric rotating sample of powder x-ray diffraction.To be mixed with the situation of A type crystallization in Type B crystallization, be specifically described, as crystallization, use pure A type crystallization as standard substance, from the characteristic peak of A type crystallization, select suitable peak (as suitable peak, the peak of such as 6.9 ± 0.2 ° can be enumerated), for this peak, the peak intensity of standard of comparison product and the peak intensity of sample to be tested, namely, by with the peak intensity of sample to be tested divided by the peak intensity of standard substance, the incorporation rate of the A type crystallization in sample can be obtained.

[table 5]

Condition determination

X-ray diffraction device: the RINT2200Ultima+/PC that Co., Ltd. of science manufactures

Assay method: collimated beam method, uses rotating sample

X-ray source: CuK α (40kV50mA)

Scan pattern: continuously

Sweep velocity: 2 °/minute

Scanning interval: 0.02 °

Turntable driving axle: θ-2 θ

Sweep limit: 3 °-40 °

Scatter slit: open

By optical slits: open

Sample bench rotating speed: 120rpm

(test example 4)

Differential Scanning Calorimeter is analyzed

Crystallization 1 ~ the 3mg obtained in the embodiment 3 and 4 of present specification is placed in open aluminium dish, use the PYRIS Diamond DSC Differential Scanning Calorimeter determinator that PerkinElmer manufactures, under a dry nitrogen atmosphere, measure to 220 DEG C by 50 DEG C with the heat-up rate of 10 DEG C/min.Or the DSC3200DSC Differential Scanning Calorimeter determinator using Bruker AXS to manufacture, measures to 220 DEG C by 50 DEG C with the heat-up rate of 10 DEG C/min.

Its result is as follows.

Measure the A type crystallization of this case compound 1 obtained according to embodiment 3, result obtains the figure shown in Fig. 4.In the Differential Scanning Calorimeter analysis of the A type crystallization of this case compound 1, confirm endotherm(ic)peak at about 182 DEG C.It should be noted that there is no special survey to the peak being shown as hydrate or solvate.

Further, measure the Type B crystallization of this case compound 1 obtained according to embodiment 4, result obtains the figure shown in Fig. 7.In the Differential Scanning Calorimeter analysis of the Type B crystallization of this case compound 1, confirm endotherm(ic)peak at about 203 DEG C.It should be noted that there is no special survey to the peak demonstrating hydrate or solvate.

In addition, the figure of crystallization prepared by embodiment 10 is also identical in fact with Fig. 4, illustrates that it is the crystallization of A type equally.Further, the figure of each crystallization prepared by embodiment 5 ~ 7 and 11 is also identical in fact with Fig. 7, illustrates that it is Type B crystallization equally.

In the present invention, though not talkative this case compound becomes hydrate or solvate just has problem especially, preferably non-hydrate (No water and thing), or be more preferably non solvate (No solvent and thing).

(test example 5)

Infrared absorption spectrum analysis

For the crystallization that the embodiment 3 and 6 according to present specification obtains, pellet technique is utilized to measure.

Its result is as follows.

Measure the A type crystallization of this case compound 1 obtained according to embodiment 3, result obtains the spectrum shown in Fig. 5.Its result, in the infrared absorption spectrum of the A type crystallization of this case compound 1, in wave number 3361cm ^-1, 2938cm ^-1, 1712cm ^-1, 1204cm ^-1, 1011cm ^-1and 746cm ^-1place confirms obvious infrared absorption band.Further, also at 3443cm ^-1, 3349cm ^-1, 1620cm ^-1, 1515cm ^-1, 1480cm ^-1or 1278cm ^-1in any place or all confirm infrared absorption band, the peak at any place among these wave numbers also can think it is at least characteristic peak.And then, also at 3473cm ^-1, 1585cm ^-1, 1432cm ^-1, 1343cm ^-1, 1159cm ^-1, 781cm ^-1or 615cm ^-1in any place or all confirm infrared absorption band, the peak at any place among these wave numbers also can think it is at least characteristic peak.

Further, measure the Type B crystallization of this case compound 1 obtained according to embodiment 6, result obtains the spectrum shown in Fig. 8.In the infrared absorption spectrum of this Type B crystallization, in wave number 2939cm ^-1, 1720cm ^-1, 1224cm ^-1, 1016cm ^-1and 751cm ^-1place confirms obvious infrared absorption band.Further, also at 3407cm ^-1, 3358cm ^-1, 1513cm ^-1, 1476cm ^-1or 852cm ^-1in any place or all confirm infrared absorption band, the peak at any place among these wave numbers also can think it is at least characteristic peak.And then, also at 3447cm ^-1, 3325cm ^-1, 1615cm ^-1, 1339cm ^-1, 1157cm ^-1, 945cm ^-1, 783cm ^-1and 617cm ^-1in any place or all confirm infrared absorption band, the peak at any place among these wave numbers also can think it is at least characteristic peak.

(test example 6)

The quantitative assay of crystallization

The A type crystallization standard substance of 0.4mg, 0.8mg, 1.2mg, 1.6mg, 2.0mg, 2.4mg, 2.8mg, 3.2mg this case compound 1 are placed in open aluminium dish, use the PYRIS Diamond DSC Differential Scanning Calorimeter determinator that PerkinElmer manufactures, under a dry nitrogen atmosphere, measure to 220 DEG C by 50 DEG C with the heat-up rate of 50 DEG C/min, obtain the area (mJ) of the endotherm(ic)peak near about 185 DEG C, that makes the crystallization of A type quantitatively uses typical curve.

And, the Type B crystallization standard substance of 0.4mg, 0.8mg, 1.2mg, 1.6mg, 2.0mg, 2.4mg, 2.8mg, 3.2mg this case compound 1 are placed in open aluminium dish, use the PYRIS Diamond DSC Differential Scanning Calorimeter determinator that PerkinElmer manufactures, under a dry nitrogen atmosphere, measure to 220 DEG C by 50 DEG C with the heat-up rate of 50 DEG C/min, obtain the area (mJ) of the endotherm(ic)peak near about 205 DEG C, that makes Type B crystallization quantitatively uses typical curve.

The typical curve of A type crystallization is shown in Fig. 9.

Further, the typical curve of Type B crystallization is shown in Figure 10.

Quantitative this point can both be carried out to the crystallization of A type and Type B crystallization to confirm.

It should be noted that, as A type crystallization standard substance, employ the crystallization that the method according to the embodiment of the present application 3 obtains, the shape of this crystallization particularly preferably, and demonstrates distinctive single endotherm(ic)peak by Differential Scanning Calorimeter analysis.Further, as Type B crystallization standard substance, employ the crystallization that the method according to the embodiment of the present application 4 obtains, the shape of this crystallization particularly preferably, and demonstrates distinctive single endotherm(ic)peak by Differential Scanning Calorimeter analysis.

(test example 7)

This case compound quantitative

Utilize following HPLC condition, carry out the detection of this case compound with quantitative.

[table 6]

Condition

Sample solution concentration: 0.2mg/mL (this case compound 1 and 3: dissolve with water/acetonitrile mixture (1: 1)

This case compound 2: dissolve with acetonitrile)

Injection volume: 10 μ L

Detector: ultraviolet light absorption photometer (measuring wavelength: 235nm)

Post: YMC-Pack Pro C18 internal diameter is 4.6mm, length is 15cm (YMC manufacture)

Column temperature: 40 DEG C

Mobile phase A: 50mmol/L SODIUM PHOSPHATE, MONOBASIC

Mobile phase B: acetonitrile

Liquor charging program: the ratio of mixture changing mobile phase A and Mobile phase B as table 7, controlled concentration gradient

Flow: 1.0mL/ minute

[table 7]

Table 7: liquor charging program

Time (minute) after injection	Mobile phase A (%)	Mobile phase B (%)
			0～45	65→20	35→80
45～60	65	35

Its result, as the hold-time, this case compound 1 confirmed peak at about 15 minutes, and this case compound 2 confirmed peak at about 30 minutes, and this case compound 3 confirmed peak at about 25 minutes.

Use this case compound standard substance separately of known quantity, obtain typical curve.Typical curve linearly.

Utilize this HPLC to confirm and can carry out quantitative assay to this case compound.

(test example 8)

To PGE during IL-1 β stimulation MG-63 cell ₂the restraining effect of generation

This case compound is investigated to the PGE caused by inflammatory stimulus matter interleukin (IL)-1 β according to the method for International Publication WO No. 03/70686 publication ₂produce the restraining effect played.

Its result, any one compound obtained by the method described in embodiment 1 ~ 9 is the PGE caused by IL-1 β of more than 50% with the control of the concentration of 0.1 μM all ₂generation.In addition, for this concentration, each testing compound does not show cytotoxic effect.Therefore, this case compound has inhibiting medicine to be useful as producing struvite prostaglandin(PG).

(test example 9)

To the prevention and therapy effect of rat assist agent arthritis

Investigate the inhibition of this case compound to the sufficient edema in rat assist agent arthritis according to the method for International Publication WO No. 03/70686 publication, rat assist agent arthritis is the pathological model of the chronic rheumatoid arthritis as one of autoimmune disorder and for chronic inflammatory diseases.It should be noted that, testing compound is suspended in the pure water containing 0.5% methylcellulose gum, by the amount of 0.1 ~ 50mg/0.2ml/kg to experimental animal oral administration.

Result shows, compared with positive controls, any one compound that embodiment 3 and embodiment 6 obtain all has restraining effect to the sufficient edema in adjuvant-induced arthritis.

Further, the death example of experimental animal is had no in this test.Therefore, this case compound is useful as the medicine that prevents and/or treats of chronic rheumatoid arthritis and autoimmune disorder.

(test example 10)

Scanning electron microscope (SEM) is observed

SEM observation is carried out to the crystallization that the embodiment 3 and 4 of present specification obtains.

Measure the A type crystallization of this case compound 1 of embodiment 3, result obtains the SEM photo shown in Figure 11.

Measure the Type B crystallization of this case compound 1 of embodiment 4, result obtains the SEM photo shown in Figure 12.

But these providing are just for the object of reference, and the characteristic of the arbitrary crystallization of the present invention is not limited to this electron microscope image, need not by these restriction.

Claims (11)

1. a crystallization, wherein, this crystallization is by 3-[3-amino-4-(1,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid formation, and this crystallization is Type B crystallization, in powder x-ray diffraction spectrum, this Type B crystallization is that 14.4 ± 0.2 °, 15.9 ± 0.2 °, 17.3 ± 0.2 °, 22.2 ± 0.2 ° and 22.9 ± 0.2 ° of places have characteristic peak at 2 θ, further, be that 8.6 ± 0.2 °, 9.8 ± 0.2 °, 21.2 ± 0.2 °, 23.6 ± 0.2 ° and 28.4 ± 0.2 ° of places have characteristic peak at 2 θ further.

2. crystallization as claimed in claim 1, wherein, be that 12.6 ± 0.2 °, 18.0 ± 0.2 °, 18.3 ± 0.2 °, 18.8 ± 0.2 °, 19.2 ± 0.2 °, 19.8 ± 0.2 °, 20.4 ± 0.2 °, 25.3 ± 0.2 °, 26.6 ± 0.2 ° and 31.8 ± 0.2 ° of places have characteristic peak at 2 θ further.

3. crystallization as claimed in claim 1 or 2, wherein, it has powder x-ray diffraction spectrum pattern identical with Fig. 6 in fact.

4. crystallization as claimed in claim 1 or 2, is characterized in that, this Type B crystallization is have the endotherm(ic)peak of about 203 DEG C in the Differential Scanning Calorimetry analysis of 10 DEG C/min at heat-up rate.

5. crystallization as claimed in claim 1 or 2, it is characterized in that, in infrared absorption spectrum, this crystallization is in wave number 2939cm ^-1, 1720cm ^-1, 1224cm ^-1, 1016cm ^-1and 751cm ^-1near there is infrared absorption band.

6. a pharmaceutical composition, it is characterized in that, this pharmaceutical composition contains the 3-[3-amino-4-(1 described in any one of Claims 1 to 5,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] the Type B crystallization of propionic acid is as effective constituent, and this pharmaceutical composition is also containing pharmaceutically useful carrier.

7. pharmaceutical composition as claimed in claim 6, it is characterized in that, described pharmaceutically useful carrier is dry thing, and described pharmaceutical composition is drying agent.

8. a pharmaceutical composition, it is characterized in that, this pharmaceutical composition contains crystallization purity and is at least the Type B crystallization of more than 90 % by weight as effective constituent, this Type B crystallization is the 3-[3-amino-4-(1 described in any one of Claims 1 to 5,2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] the Type B crystallization of propionic acid, this pharmaceutical composition is also containing pharmaceutically useful carrier.

9. 3-[3-amino-the 4-(1 described in any one of Claims 1 to 5, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] manufacture method of Type B crystallization of propionic acid, it is characterized in that, by 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid is dissolved in and is selected from by acetone, methylene dichloride, methyl alcohol, ethyl acetate, in any one or two or more solvents in the group of methyl alcohol/acetic acid mixture and acetonitrile composition, this 3-[3-amino-4-(1 is made from the solution dissolved, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] propionic acid crystallization.

10. 3-[3-amino-the 4-(1 described in any one of Claims 1 to 5, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] manufacture method of Type B crystallization of propionic acid, it is characterized in that, 3-[3-amino-4-(1 in the basic conditions, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base)-phenyl] acid adding in propionic acid solution, be about to generate by this 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base)-phenyl] propionic acid form crystallization before, the Type B crystallization of this compound is added as crystal seed when pH is 7 ~ 9 in system, obtain the Type B crystallization of this compound thus.

11. 3-[3-amino-4-(1 as claimed in claim 10, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] manufacture method of Type B crystallization of propionic acid, it is characterized in that, 3-[3-amino-4-(1 under described alkaline condition, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base)-phenyl] propionic acid solution is 3-[3-amino-4-(1, 2-indane-2-base oxygen base)-5-(1-methyl isophthalic acid H-indazole-5-base) phenyl] carbonatoms of propionic acid is the alkaline hydrolysate of the alkyl ester of 1 ~ 4.